Motor training with brain plasticity

ABSTRACT

A rehabilitation device, comprising a movement element capable of controlling at least one motion parameter of a portion of a patient; a brain monitor which generates a signal indicative of brain activity; and circuitry including a memory having stored therein rehabilitation information and which inter-relates said signal and movement of said movement element as part of a rehabilitation process which utilizes said rehabilitation information.

RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.11/660,965 filed on Jan. 8, 2009, which is a National Phase of PCTPatent Application No. PCT/IL2005/000906 filed on Aug. 18, 2005, whichis a continuation-in-part of PCT Patent Application Nos.PCT/IL2005/000442 filed on Apr. 28, 2005; PCT/IL2005/000135;PCT/IL2005/000136; PCT/IL2005/000137; PCT/IL2005/000138;PCT/IL2005/000139 and PCT/IL2005/000142 all filed on Feb. 4, 2005. Thecontents of the above applications are incorporated herein by reference.

U.S. patent application Ser. No. 11/660,965 also claims the benefit ofpriority of U.S. Provisional Patent Application Nos. 60/686,991 filed onJun. 2, 2005; 60/633,429 filed on Dec. 7, 2004; 60/633,428 filed on Dec.7, 2004; 60/633,442 filed on Dec. 7, 2004 and 60/604,615 filed on Aug.25, 2004.

This application is also related to U.S. Provisional Patent ApplicationsNos. 60/666,136 filed Mar. 29, 2005; 60/665,886 filed Mar. 28, 2005 andU.S. patent application Ser. No. 11/207,655 filed Aug. 18, 2005, thecontents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention is related to the field of motor and/or cognitive,training and/or rehabilitation, for example rehabilitation utilizingbrain activity measurements.

BACKGROUND OF THE INVENTION

Following is a short introduction to measurement of some types ofelectrical brain activity associated with motor control and what iscurrently believed to be their meaning. It should be noted thatapplication of the invention is not necessarily constrained by thesemeanings and other signals may be measured and/or the following signalsbe used in other ways. Various articles are listed at the end of thebackground section.

Movement-Associated Cortical Potential (MAC) Accompanying VoluntaryMovement

Experiments have shown that every voluntary movement is associated withan electrical cortical potential that can be recorded over the scalp.This activity is typically characterized by three components:

-   -   1. The “Bereitschaftspotential” (BP) or “Readiness Potential”        defined as a slowly ‘rising’ negative potential that occurs 1-2        seconds prior to volitional self-initiated movements. It is        related to the preparatory process prior to limb movement. This        BP consists in fact of two components:        -   an early component (BP1) that lasts from the very beginning            of the BP (starting 1-2s or more prior to movement onset            depending on the complexity of the movement) to            approximately 0.5s before movement onset; and        -   a late component (BP2) that occurs for the last half second            before onset (see FIG. 1). BP2 has a steeper negative slope            than BP1.    -   2. The motor potential (MP) which consists of an initial sharp        negative deflection that follows the BP's more gradual        negativity. This potential is related to motor activity. At        movement onset (at t=0 as shown in FIG. 1 below), there exists a        sharp positive inflection that peaks at around 200 ms after the        movement onset. This period is typically contaminated with EMG        artifacts.    -   3. The post-movement activity (PMA) which is the potential        change (starting more than 200 ms after the movement onset)        whereby the brain resynchronizes and resumes ‘normal’ activity.

FIG. 1 presents an averaged Motor Related Potential (MRP) template thatillustrates these distinguishable periods. This in an example of anaveraged MRP recorded for 918 left finger movement trials (onset at t=0)at C3 (channel 3) and C4 (channel 4).

For unilateral movement, BP1 typically has a symmetric and bilateraltopography on the scalp, i.e. it is not lateralized about the motorcortex.

In contrast BP2 is typically larger (more negative) over the primarymotor area of the contra lateral hemisphere. This is evident in FIG. 1for the last ˜200 ms prior to finger press at time t=0. The electrode C4is positioned on the right side of the head and for the left fingermovement as shown exhibits a more negative potential on average than thecontra-laterally placed C3 electrode.

Rich experimental evidence indicates that BP1 and BP2 might involvedifferent functional systems. Experiments in PET (Positron EmissionTomography) and unicellular recordings in monkeys suggested that partsof the mesial frontal cortex, and typically the Supplemental Motor Area,may be involved in the generation of BP1. On the other hand, severalinvestigators concluded that BP2 potential reflects expression of nerveexcitation, namely, activity of cortical-spinal tract concerningefferent discharges of pyramidal tract.

It has been suggested that the awareness of willingness to move occurredlater than the beginning of the electrophysiological event and that,consequently, the first part of the decision process to move wasinfra-conscious, at least for self-paced tasks.

All the above supports the fundamental EEG theory that potentialnegativity can be related to activity of the cortical areas whereaspositivity is related to inactivity. Since the extremities of the humanbody are controlled by the contra lateral side of the brain it isgenerally expected that there should be more activity and hence‘negativity’ on the contra lateral side. However, it should be notedthat this is not always the case.

It has been shown that, the signal distribution over the scalp of theBP2 potential shows maximum at C3, (central left scalp), in case ofvoluntary right upper arm flexion movement. The maximum was at C4,(central right scalp), in case of voluntary left upper arm flexionmovement. The distribution of the late PMA potential showed maximum atCz, (central medial) in case of voluntary right or left upper armflexion movement. The only part of the MAC that shows potentials contralateral to the side of the movement is BP2.

Contingent Negative Variation (CNV)

In some experimental setups the generation of a MAC potential involvesthe performance of a prescribed task under the prompting of a pair ofcuing stimuli: S1 and S2, separated by a given time interval. The firstcue, (S1), is a ‘warning’ or ‘preparatory’ cue which is subsequentlyfollowed by a second ‘imperative’ cue (S2).

The subject is instructed to perform the given task as fast as possiblefollowing the presentation of the imperative stimulus (S2). Briefly, thepreparatory stimulus precedes the imperative and thus acts as a ‘getready’ signal to warn the subject that the imperative stimulus isapproaching.

Under these conditions, the resultant waveform recorded over the scalpis a slow negative shift beginning at the presentation of S1 and endingroughly at the presentation of S2.

FIG. 2 shows a typical event-related potential in an S1-S2 paradigm,measured from central derivations (average of C3 and C4). The x-axisshows the presentations of S1 (onset at time t=0), and S2 (onset at t=6seconds). The measures for PSW, NSW, and CNV (shown on the figure) asused in the present study are indicated.

The task can be, for instance, that S1 is a sound which the subject hadto decide if it belongs to a previously memorized set of sounds. Theresult of this memory search task indicates the response instructionexpected at S2; for instance, that a response has to be given eitherwith the left or with the right hand, depending on the result of thesearch.

Referring back to FIG. 2, within the first second after S1 a slow wavecomplex can be seen which consists of a positive (slow wave) deflection(the “PSW”).

Later in the S1-S2 interval, a slow negative shift develops, whichreaches a negative maximum immediately before S2. This shift is calledthe contingent negative variation (CNV).

When the S1-S2 interval is sufficiently long, three seconds or more, thenegative shift clearly consists of two parts. The first part, callednegative slow wave (NSW), is maximal at the frontal positions, betweenabout 0.5 and 1 second after S1.

PSW has a parietal dominance and is assumed to reflect the outcome ofstimulus evaluation and has been found to attenuate when the task ismore difficult.

NSW has a frontal maximum, and some authors have found that it islateralized in the right hemisphere. It is often regarded as part of anorientation reaction, because it is affected by the physicalcharacteristics of S1, such as intensity, probability, and modality. TheNSW is larger when the task at S1 is more difficult.

The CNV is mainly related to motor response preparation; its amplitudedepends heavily on the task demands at S2, and is affected by taskvariables as speed/accuracy instructions, and the duration of the S1-S2interval. CNV has the largest amplitude at the central electrodes.

CNV and Readiness Potential (BP)

CNV and BP are often considered to reflect the same process, since theyare maximal at the same positions on the scalp, and immediately before aresponse is given. The difference between CNV and BP is, however, thatthe first is derived as a stimulus-locked potential, whereas the latteris derived relative to the response.

Whereas the BP is specific to motor readiness, and is concentrated overthe primary motor cortex, the CNV is associated with more cognitiveaspects of anticipation, and is generally localized to frontal andfrontal-central cortex.

Topographic Plots of Bereitschafts Amplitudes with Different Types ofMovement

In order to get a good picture of overall Motor Related Potentialdistribution effects, including lateralization effects, experimentersemploy a two dimensional interpolation scheme from data collectedthrough a multiple electrode arrangements. This technique facilitatesthe visualization of the topographic distribution of BP amplitudes overthe entire scalp surface.

(Briefly, the data processing method consists of: first, the amplitudeof the total negativity is measured algorithmically for each electrodeposition of the whole scalp arrangement. Because the data includes alarge amount of high-frequency noise, a mean of 20-50 ms of voltage datais used to estimate the potential at the start and end of each BPwaveform. The end value is then subtracted from the start value, thusyielding (in most cases) a positive magnitude for the negativity. Thesedata is then combined with the known relative coordinates of eachelectrode to generate a two-dimensional grid interpolation of theoverall negativity values. In addition, before the interpolation isapplied, the EOG and EMG electrodes are removed from the data set astheir given coordinates are figurative and they generally showed noevidence of significant waveforms.)

Free Movement

If subjects are asked to initiate a voluntary extension of the middleand ring fingers necessary and sufficient for production of a reliableExtensor Communis EMG signal of the right hand only, the recorded MAC isas in FIG. 3 (left) and the topographic distribution of the signalfollowing the data processing described above is as in FIG. 3 (right).

CP2 (central parietal 2, slightly to the right of the central line andjust below towards the back of the brain, relative to the point in FIG.1). In the graph in FIG. 3 left shows the activity contra lateral to themovement. The translation of color into gray scale is as follows: Colorsare gradual changing values. The two rounded dark areas in the centerare positive peaks and the other dark areas are negative peaks.

In this case the voluntary movements are completely at the will of theparticipant, although a rough guideline is given to the subject to leaveat least two to three seconds between movements. Accordingly, we can seemost of the features described previously.

Synchronized Movement

If instead of moving the finger at will the subject is to initiatemovement according to a self-maintained, even, metrical pulse with arough guideline frequency of around 0.5 Hz, the resulting potentials aredifferent. Ideally this will produce MAC events at the steady, regularrate of 0.5 Hz. These events should be phase locked to the subject'sinternal pulse. This is a ‘synchronize’ condition.

The resulting topographical maps are shown in FIG. 4 where BP amplitudeis visualized as a color spectrum mapping (shown as grey scale). Inthese plots, a clear distribution effect of the experimental conditionis even more evident than in the previous case of free movement. Thedark area on the bottom is positive values and the dark area on the topis negative values.

As before, the movement consisted in the extension of the middle andring fingers of the right hand sufficient for production of a reliableExtensor Communis EMG signal. It is clear that in this condition, thespread is mostly towards the left side of the head.

Applying the topographic algorithm described in the previous section,(mean of 20-50 ms of voltage data at beginning and end each signal), itcan be seen that there are two spots of maximal amplitude of the wholesignal: one is central and the other is slightly to the side contralateral to the movement.

Syncopate Movement

In this case, the subject is again instructed to maintain an internalmetrical pulse. However, in this trial the subject is instructed toinitiate finger movements exactly counter to the pulse. That is, themovements should be phase shifted by half a period from the maintainedinternal pulse. Ideally this will produce MAC events at a frequency of0.5 Hz, phase-shifted by 1 second from the internal pulse. This is the‘syncopate’ condition. Results are shown in FIG. 5. (high values are atthe bottom of the image, low on top).

From FIGS. 3-5 it can be seen that a clear distribution of theexperimental condition is evident. First, there is an apparent spreadingin the location of maximum BP amplitude in all the experimentalconditions relative to the “Free Movement” condition. In the“Synchronized” conditions, the spread is mostly towards the left side ofthe head. In the “Syncopate” condition some spread to the right side isalso present.

One potential effect is the appearance of CNV in the syncopateconditions. As described in a previous section, CNV usually marksexpectation or anticipation in non-motor regimes.

Motor Imagery as Activator of Cortical Activation

Very recently a technique named “mirror therapy” has been reported to beused to activate unused cortical networks and help to reduce the painassociated with cortical abnormalities following injury as occurs inphantom pain and stroke. Briefly, “mirror therapy” involves the movementof a limb inside a mirror box such that visual feedback of the affectedhand is replaced by that of the (reflected) unaffected hand. There istherefore an attempt to reconcile motor output and sensory feedback andto activate pre-motor cortices. In his last article, Moseley 2004writes: “The mechanism of the healing effect of this technique, althoughnot clear, may involve the sequential activation of cortical pre-motorand motor networks, or sustained and focused attention to the affectedlimb, or both.”

Slow Cortical Potential (SCP)

SCP in general has been extensively used by Prof. Neils Birbaumer andhis group in the University of Tuebingen, Germany. SCPs are potentialshifts in the scalp-recorded EEG that occur over 0.5-10 sec. Negativeand positive SCPs are typically associated with functions that involvecortical activation and deactivation, respectively. Healthy subjects andneurological patients can attain reliable control over their SCPsamplitude and polarity recorded at frontal and parietal locations bymeans of sensory (e.g., visual and audio) feedback. In addition,subjects can learn to control SCP differences between the left and righthemisphere.

Mu Rhythm

When a person is at rest, his sensorimotor cortex generates an 8-13 Hzelectro-encephalographic rhythm referred to as the “Rolandic mu rhythm”.As soon as the person starts to execute a movement and the motor cortexis activated, the mu rhythm is attenuated or disappears. The mu rhythmis present in most, if not all, adults, it is generated by athalamo-cortical network and it is strongest when no active processingis occurring. Decreases in mu amplitude possibly indicate that theunderlying cell assemblies have become desynchronized (hence, lower murhythm amplitudes are recorded over the scalp). The mu rhythm alsodesynchronizes when subjects are only observing (but not executing) amovement and the degree of desynchronization reflects the level ofactive processing; for instance, it is greater when a person isperforming a precision grip than during the performance of a simple handextension. These rhythms also respond to imagination of movement in apattern similar to that during the planning of a movement. For instance,subjects with limb amputation that mentally mobilize the missing limb,show a blocking effect of mu rhythm while imagining the movement.

Feedback training leads to increase in mu desynchronization; and theability of subjects to manipulate the sensorimotor mu rhythm has beenrecently used by Wolpaw et al. group to act as a brain—computerinterface based on a binary signal. For instance, subjects can learn toproduce similar or differential mu activity over the two hemispheres inorder to control left or right movement in a three-dimensional videogame.

Sometimes differences of amplitude in both hemispheres are recorded fortwo frequency band rhythms to allow for a bi-dimensional movement overthe screen. For instance, in Wolpaw et al (Jonathan R. Wolpaw and DennisJ. McFarland 2004. Control of a two-dimensional movement signal by anoninvasive brain—computer interface in humans. PNAS 2004, vol. 10, no.51: 17849-17854), the disclosure of which is incorporated herein byreference, use vertical movement of a cursor was controlled by a 24-Hzbeta rhythm and horizontal movement by a 12-Hz mu rhythm recorded atleft- and right-side scalp electrodes locations C3 and C4 over thesensorimotor region. Vertical correlation is greater on the left side,whereas horizontal correlation is greater on the right side.

FIG. 9 shows on the left the various positions on the screen towardswhich the user learns to move the cursor from a center position. Oncenter/right of FIG. 9 there are the recordings of brain potential whena user tries to move to Target 1 (up), Target 6 (down), Target 3 (right)and Target 8 (left). It can be seen, for instance, that in order to moveto Target 1 (up) the user needs to increase Beta rhythm (24 Hz) recordedover the C3 and in order to move to Target 8 (left) the user needs toreduce the mu rhythm (12 Hz) recorded over the C4 region. In the figure,vertical control has two positive peaks as shown, while in horizontalcontrol, the left peak is a negative peak and the right peak is apositive peak.

Many studies have demonstrated that humans can learn to control μ-rhythmamplitudes independent of actual movement and use that control to move acursor to targets on a computer screen (Walpow et al., 1991; McFarlandet al., 1993; Pfurtscheller et al., 1993), or to control an artificialhand attached to the paretic hand (Pfurtscheller et al., 2003). None ofthese studies, apparently was conducted in stroke patients or otherpatients with brain damage, such as that due to traumatic brain injury.

Cortical Reorganization after Stroke

Return of voluntary arm movements is one of the most important goalsduring stroke rehabilitation to avoid long-term disability in activitiesof daily living (ADL) function.

Some studies have demonstrated recruitment of areas adjacent to thebrain lesion or ipsilateral motor regions of the unaffected hemisphereafter complete recovery from upper extremity motor impairment. Rossiniet al. (1998) for example, who used brain imaging methods as functionalmagnetic resonance imaging (fMRI), transcranial magnetic stimulation(TMS), and magnetoencephalography (MEG) to examine a patient who fullyrecovered after stroke, found an asymmetrical enlargement and posteriorshift of the sensorimotor areas localized in the affected hemispherewith all three techniques.

Nelles et al. (1999), used serial positron emission tomography (PET) tostudy the evolution of functional brain activity within 12 weeks after afirst subcortical stroke. Six hemiplegic stroke patients were scannedtwice (PET 1 and PET 2). At PET 1, activation was observed in thebilateral inferior parietal cortex, contralateral sensorimotor cortex,and ipsilateral dorsolateral prefrontal cortex, supplementary motorarea, and cingulate cortex. At PET 2, significant increases of regionalcerebral blood flow were found in the contralateral sensorimotor cortexand bilateral inferior parietal cortex. A region that was activated atPET 2 only was found in the ipsilateral premotor area. Based of theirfindings, Nelles et al conclude that recovery from hemiplegia isaccompanied by changes of brain activation in sensory and motor systems,and that these alterations of cerebral activity may be critical for therestoration of motor function.

Johansen-Berg et al. (2002) examined seven stroke patients with fMRItwice before and twice after a home-based two weeks rehabilitativetherapy. They found that therapy-related improvements in hand functioncorrelated with increases in fMRI activity in the premotor cortex andsecondary somatosensory cortex contralateral to the affected hand, andin superior posterior regions of the cerebellar hemispheres bilaterally.As the former studies, these results suggest that activity changes insensorimotor regions are associated with successful motorrehabilitation.

In addition, accumulating evidence in stroke patients suggests thatrehabilitation techniques with repetitive training of functionalmovements have significant effects on recovery of motor skills andcortical reorganization. Lipert et al. (2000), for example, evaluatedreorganization in the motor cortex of stroke patients that was inducedwith an efficacious rehabilitation treatment. Before treatment, thecortical representation area of the affected hand muscle wassignificantly smaller than the contralateral side. After a 12-day-periodof constraint-induced movement therapy, the muscle output area size inthe affected hemisphere was significantly enlarged, corresponding to agreatly improved motor performance of the paretic limb. Shifts of thecenter of the output map in the affected hemisphere suggested therecruitment of adjacent brain areas. In follow-up examinations up to 6months after treatment, motor performance remained at a high level,whereas the cortical area sizes in the 2 hemispheres became almostidentical, representing a return of the balance of excitability betweenthe 2 hemispheres toward a normal condition.

Luft et al. (2004) tested whether specific rehabilitation therapy thatimproves arm function in stroke patients is associated withreorganization of cortical networks. Patients were randomly assigned tobilateral arm training (n=9) or standardized dose-matched therapeuticexercises (n=12). Both were conducted for 1 hour, 3 times a week, for 6weeks. Within 2 weeks before and after the intervention, brainactivation during elbow movement was assessed by fMRI and functionaloutcome was assessed using arm function scores. Patients in the firstgroup (bilateral arm training) but not in the second group increasedhemispheric activation during paretic arm movement. Significantincreased activation was observed in the contralesional cerebrum andipsilesional cerebellum. These findings suggest that bilateral armtreatment induces reorganization in contralesional motor networks andprovide biological plausibility for repetitive bilateral training as apotential therapy for upper extremity rehabilitation in hemipareticstroke.

Summary

Numerous studies have demonstrated that the damaged brain is able toreorganize to compensate for motor deficits. Rather than a completesubstitution of function, the main mechanism underlying recovery ofmotor abilities involves enhanced activity in preexisting networks,including the disconnected motor cortex in subcortical stroke and theinfarct rim after cortical stroke. Involvement of nonmotor andcontralesional motor areas is consistently reported, with the emergingnotion that the greater the involvement of the ipsilesional motornetwork, the better is the recovery. A better stroke recovery seems totake place if the changes in certain brain areas over time are such thatthe normal balance between the 2 hemispheres tends to reestablish. Thus,recovery is best when the brain regions that normally execute thefunction are reintegrated into the active network. Consistent with thisview, intense rehabilitative procedures (both active and passive) haverecently been shown to enhance activation of the ipsilesional motor areain parallel with improved motor function.

Consistent results were a dynamic reorganization that went along withrecovery, over-activation of motor and non-motor areas in bothhemispheres regardless of whether the task was active or passive leadingto a decrease in the laterality index, and a return toward a more normalintensity while the affected hand regained function (Calautti and Baron,2003). In some embodiments of the invention, as described below, suchresults are achieved using methods and apparatus as described herein.

Some components of brain activity (e.g., SCPs) can be controlled byincreasing or decreasing the general brain activity, independent fromthe recorded site. Subjects can learn to control SCP differences betweenthe left and right hemisphere (Rockstroh et al., 1990).

Brain-Computer Interface (BCI)

A BCI system measures particular components of features of EEG activityand uses the results as a control signal. Present-day BCIs determine theintent of the user from a variety of different electrophysiologicalsignals. These signals include slow cortical potentials (SCP), P300potentials, and μ (mu) or beta rhythms recorded from the scalp, andcortical neuronal activity recorded by implanted electrodes (referred asBrain-Machine Interface, BMI). They are translated in real-time intocommands that operate a computer display or other device.

A BCI converts a signal such as an EEG rhythm or a neuronal firing ratefrom a reflection of brain function into the end product of thatfunction: an output that, like output in conventional neuromuscularchannels, accomplishes the person's intent. A BCI replaces nerves andmuscles and the movements they produce with electrophysiological signalsand the hardware and software that translate those signals into actions.

Many studies have demonstrated that healthy subjects and neurologicalpatients can attain reliable control over their slow cortical potentials(SCPs) amplitude at vertex, frontal and parietal locations with operantlearning. Moreover, subjects can learn to control SCP differencesbetween the left and right hemisphere (Birbaumer et al., 1999; Birbaumeret al., 1988; Rockstroh et al., 1990). Successful learning usingreinforcement and shaping of the response results in the acquisition ofa new, non-motor skill (Birbaumer et al., 1999). Studies involvingmu-rhythm (Walpow et al, 2002) confirm and extend these findings.

The following articles, some of which are referenced herein, have theirdisclosures incorporated herein by reference:

-   International Journal of Psychphysiology 9 (1990) 151-165    “Biofeedback-produced hemispheric asymetry of slow cortical    potentials and its behavioural effects”, by B Rockstroh, T Elbert, N    Birbaurmer and w Lutzenberger.-   Wolpaw, J. R., McFarland, D. J., Neat, G. W. and Forneris, C. A. “An    EEG-based brain-computer interface for cursor control”    Electroenceph. din. Neurophysiol., 1991, 78:252-259.-   McFarland, D. J., Neat, G. W., Read, R. F. and Wolpaw, J. R. “An    EEG-based method for graded cursor control” Psychobiology, 1993, 21:    77-81.-   Pfurtscheller, G., Flotzinger, D. and Kalcher, J. “Brain-computer    interface: a new communication device for handicapped persons”    Journal of Microcomputer Applications, 1993, 16:293-299.-   “Arm Training Induced Brain Plasticity in Stroke Studied with Serial    Positron Emission Tomography” G. Nelles, W. Jentzen, M. Jueptner, S.    Muller, and H. C. Diener. Neurolmage 13, 1146-1154 (2001)    doi:10.1006/nimg.2001.0757.-   “Control of a two-dimensional movement signal by a noninvasive    brain—computer interface in humans” Jonathan R. Wolpaw and Dennis J.    McFarland. PNAS Dec. 21, 2004 vol. 101 no. 51 17849-17854-   “‘Thought’—control of functional electrical stimulation to restore    hand grasp in a patient with tetraplegia” Gert Pfurtschellera,    Gernot R. Mu{umlaut over ( )}ller, Jo{umlaut over ( )}rg    Pfurtscheller, Hans Ju{umlaut over ( )}rgen Gernerd, Ru{umlaut over    ( )}diger Ruppd. Neuroscience Letters 351 (2003) 33-36-   Nelles G, Spiekermann G, Jueptner M, Leonhardt G, Muller S, Gerhard    H, Diener H C. “Evolution of functional reorganization in hemiplegic    stroke: a serial positron emission tomographic activation study” Ann    Neurol 1999; 46:901-909-   “Hand motor cortical area reorganization in stroke: a study with    fMRI, MEG and TCS maps” P. M. Rossini, C. Caltagirone, A.    Castriota-Scanderbeg, P. Cicinelli, C. Del Gratta, M. Demartin, V.    Pizzella, R. Traversal and G. L. Romanil. NeuroReport 9, 2141-2146    (1998)-   “Correlation between motor improvements and altered fMRI activity    after rehabilitative therapy” Heidi Johansen-Berg, Helen Dawes,    Claire Guy, Stephen M. Smith, Derick T. Wade and Paul M. Matthews.    Brain (2002), 125, 2731-2742-   “Treatment-Induced Cortical Reorganization After Stroke in Humans”    Joachim Liepert, M D; Heike Bauder, PhD; Wolfgang H. R. Miltner,    PhD; Edward Taub, PhD; Cornelius Weiller, M D (Stroke. 2000;    31:1210-1216.)-   Birbaumer, N. et al. (1999). “A spelling device for the paralysed.”    Nature 398(297-298).-   Birbaumer, N., et al. (1988). “Slow brain potentials, imagery and    hemispheric differences.” International Journal of Neuroscience 39:    101-116.-   Rockslroh, B., et al. (1990). “Biofeedback-produced hemispheric    asymmetry of slow cortical potentials and its behavioral effects.”    International Journal of Psychophysiology 9(2): 151-165.-   Wolpaw, J. R., Birbaumer, N., McFarland, D. J., Pfurtscheller, G.,    Vaughan, T. M., 2002. Brain/computer interfaces for communication    and control. Clinical Neurophysiology 113, 767-791.-   Ward N S, Brown M M, Thompson A J, Frackowiak R S. Neural correlates    of outcome after stroke: a cross-sectional fMRI study. Brain 2003;    126:1430-1448.-   “Repetitive Bilateral Arm Training and Motor Cortex Activation in    Chronic Stroke A Randomized Controlled Trial” JAMA. 2004;    292:1853-1861-   “Functional Neuroimaging Studies of Motor Recovery After Stroke in    Adults A Review” Cinzia Calautti, M D; Jean-Claude Baron, M D, FRCP,    FMedSci (Stroke. 2003; 34:1553-1566.)

SUMMARY OF THE INVENTION

A broad aspect of some embodiments of the invention relates torobot-assisted rehabilitation which utilizes EEG or other assessment ofbrain activity. In an exemplary embodiment of the invention, theassessment is used to induce and/or measure brain plasticity. In anexemplary embodiment of the invention, brain and manipulator functionare correlated or interact, for example, using one to trigger orgenerate the other.

In an exemplary embodiment of the invention, measurements of brainactivity are used to provide feedback to one or more of patient, systemand/or therapist, for example, during an exercise, during a sessionand/or between sessions. In an exemplary embodiment of the invention,the cortical effect of a rehabilitation exercise is thus assessed and/oroptionally correlated with physical effect of the rehabilitation. Thismay be used to identify problems in the rehabilitation process and/orpatient limitations. In an exemplary embodiment of the invention, thefeedback is used for more cortically specific rehabilitation, in whichrehabilitation exercises and/or parameters are used to selectively focuson certain brain areas and/or restructuring methodologies. Optionally,an exercise is used if it shows a desired selective, cortical and/orrestructuring effect. The exercise is optionally dropped, reduced inimportance and/or its parameters changed, if a desired effect is notfound.

In an exemplary embodiment of the invention, the rehabilitation is usedto obtain an improvement effect on motion and/or on a desire to carryout a motion.

In an exemplary embodiment of the invention, a goal of rehabilitation isto improve an innate cortical ability and/or matching between corticalability and physical ability. Optionally, this rehabilitation includesperforming a plurality of exercises (typically over 100, over 1000 orover 10,000, or intermediate numbers, within a short period of time,such as less than 1 month, less than one week or intermediate times),optionally with many exact or approximate repetitions and modifying anexercise parameter according to improvement in function. Optionally,safety considerations are applied during rehabilitation. Optionally, therehabilitation is under supervision of a physical therapist. Typicallyone or more rehabilitation goals are provided, for example a percentimprovement in control of a limb and/or activity.

A broad aspect of some embodiments of the invention relates to assistingcognitive rehabilitation using a robotic manipulation system.

In an exemplary embodiment of the invention, selective treatment ofbrain areas is provided. In an exemplary embodiment of the invention, amanipulation and measurement system optionally as described herein isused to identify the edge of a damaged area in the brain, so thatplasticity and rehabilitation efforts may focus on that area.Optionally, such an edge area is identified by its having a raggedactivation profile.

In an exemplary embodiment of the invention, local activation isprovided, for example, by one or more of heating, magnetic brainstimulation, electrical stimulation and/or drug delivery. In anexemplary embodiment of the invention, selective activation of therelevant brain area is provided by cognitive feedback training of thepatient to activate a brain area and then provision of a drug or othergeneralized treatment. Optionally, such selectively is applied before,during and/or after a physical rehabilitation exercise which addressesthat area. Optionally, the timing and/or relative triggering areprovided by a manipulator system which measures brain activity and/orphysical activity.

In an exemplary embodiment of the invention, a manipulation device isused for providing direct cortical rehabilitation. In an exemplaryembodiment of the invention, SCP signals recorded from a single point ofthe scalp, (for instance Cz), are used in a biofeedback fashion to teachthe patient to control the negativity (cortical activation) orpositivity (cortical deactivation) of the signal at that point. Once thepatient is able to control the SCP signal at a single point, one featureof the signal (for instance its negativity) is optionally used to drivea manipulator in space, for example, in a mono-directional fashion inone plane. Later, after further progress of the patient, optionally, thevarious features of the signal are translated into a binary code used todrive the manipulator in space in a mono-directional fashion in oneplane. Later after yet further progress, optionally, by measuring atvarious different points over the scalp, the patient is trained tocontrol the SCP signal at each one of them simultaneously and thatinformation is translated into binary codes used to teach the patient todrive the manipulator in space in a multidirectional fashion;optionally, first in a single plane and later in a three dimensionalmode. The manipulator may be used for one or both of producing amovement as a response to the particular combination of cortical signalsand/or enhance and amplifying traces of movement conquered by thepatient. Optionally, the patient is selectively instructed to try andcarry out motions and/or image the motions.

A broad aspect of some embodiments of the invention, relates to the useof a manipulator to improve measurement capabilities. In an exemplaryembodiment of the invention, repetitive or selectively different motionsby the manipulator are used to better detect brain activation and/ortease apart different sources of brain activity.

In an exemplary embodiment of the invention, repetitive specific motionis used to define a cortical signal, for example, for comparison or fordeciding on treatment. In an exemplary embodiment of the invention, thefact that a repetitive manipulator is used, allows brain signalsrecorded over multiple trials to be combined and averaged. Optionally,the manipulator is used to trigger the movement, so that the signals canbe aligned in time. Optionally, the motion includes motion of a healthyarm and of a paretic arm. The healthy arm movements are optionallydetected by the manipulator and used as the above trigger.

An aspect of some embodiments of the invention relates to using arobotic manipulator to provide incorrect or partial motions. In oneexample, the robotic manipulator applies force which is contrary to amotion planned by a patient. This may be used, for example, forassessment, by measuring the patient response, or as training toovercome physical obstacles or train certain brain areas. In anotherexample, a robotic manipulator starts a motion and then becomes passive,or less active, to see if the patient can compensate or complete amotion on its own. In another example, the manipulator can be used toallow a patient (or therapist) to plan motion and/or make changes inplanned motions, so that the patient can experience motions andcognitive activates not otherwise possible. Optionally, after suchplanning, the motion is executed or the patient is assisted with themotion. Optionally, a graphical interface is used for such planning orchanging. Alternatively or additionally, a physical interface of themanipulator making a motion or a patient moving the manipulator, is usedas an input device by the patient. Optionally, brain activity duringsuch planning is also measured and optionally shown to the patient(e.g., directly or in simplified form) as feedback or to show progressin planning ability.

An aspect of some embodiments of the invention relates to dailyassessment of mental state as part of rehabilitation. In an exemplaryembodiment of the invention, brain image, blood tests and/or EEGmeasurements are used to assess an instant mental state of a patient,for example, depression. Optionally, depending on the motivational stateof the patient additional motivation may be provided and/or lesserachievements may be expected. It should be noted that this type ofdepression relates to a mood, which can change hourly or daily and notto clinical depression which is a long term illness.

In an exemplary embodiment of the invention, cognitive rehabilitationprogress is assessed using other means, such as problem solving or othercognitive tests. Optionally, cognitive progress is used to calibrateexpected physical rehabilitation progression

An aspect of some embodiments of the invention relates to ensuringand/or confirming a correct mental imagery by a patient by actuallycarrying out the motion or a similar motion for the patient. In somecases, damage to the brain may make such imaging difficult orimpossible. In other cases, it is not clear if the patient correctlyunderstood instructions. In an exemplary embodiment of the invention,the presented motion can then be compared exactly to an actually carriedout motion. In this and other embodiments of the invention, a roboticmanipulator may be replaced by one or more position and/or orientationsensing devices and having a human move the patient and the motion betracked by the position sensing device. However, an advantage of arobotic manipulator is being able to define ahead of time what themotion or motion response will be, which is generally not as precisewith a human manipulator.

In an exemplary embodiment of the invention, the mental imagery isstimulated using instruction (even with eyes closed) and/or presenting amovie or actual motion. Optionally, the movie is of the patient himselfmoving. Optionally, what is shown is a process image, for example, amirror image of a motion carried out using a healthy arm, for a pareticarm.

In an exemplary embodiment of the invention, the provided motion is apartial motion or only includes hints, for example, stopping pointsalong the motion rather than a complete motion. Optionally, a motionthat is intentionally different to what is to be done, is used, forexample, to force the patient to carry out mental manipulation (e.g.,translation and/or rotation) of a motion in his head.

Optionally, the motion used for the guided mental imagery is changed,for example, to prevent habilitation of the patient thereto.

An aspect of some embodiments of the invention relates to using a dosagescheme for rehabilitation. In an exemplary embodiment of the invention,the dosage scheme relates to one or both of the effect on a patientand/or the activity of the patient, rather than merely time spent. In anexemplary embodiment of the invention, dosage control is applied inwhich a minimum exertion (mental and/or physical) and/or attention levelare required. Alternatively or additionally, a desired level and/or amaximum level are proscribed. In an exemplary embodiment of theinvention, a rehabilitation system monitors the actual applied dosagefor one or both of calculating billing and ensuring dosage compliance.

There is thus provided in accordance with an exemplary embodiment of theinvention, a rehabilitation device, comprising:

a movement element capable of controlling at least one motion parameterof a portion of a patient;

a brain monitor which generates a signal indicative of brain activity;and

circuitry including a memory having stored therein rehabilitationinformation and which inter-relates said signal and movement of saidmovement element as part of a rehabilitation process which utilizes saidrehabilitation information.

Optionally, said portion is a limb.

In an exemplary embodiment of the invention, said circuitry controlssaid movement element.

In an exemplary embodiment of the invention, said circuitry controls atleast one of the direction and location of a movement or a reach point.

In an exemplary embodiment of the invention, said circuitry controls atleast one of resistance to movement, speed and movement mode.

In an exemplary embodiment of the invention, said circuitry measures atleast one parameter of motion of said movement element. Optionally, saidcircuitry measures at least one of force, movement vector and speed ofsaid movement.

In an exemplary embodiment of the invention, said rehabilitationinformation comprises a rehabilitation plan.

In an exemplary embodiment of the invention, said rehabilitationinformation comprises a rehabilitation diagnosis.

In an exemplary embodiment of the invention, said rehabilitationinformation comprises at least one template of expected brain-motionrelationship.

In an exemplary embodiment of the invention, said circuitry is adaptedto generate an expected motion based on said measurement.

In an exemplary embodiment of the invention, said circuitry is adaptedto generate an expected brain activity based on movement of saidmovement element.

In an exemplary embodiment of the invention, said circuitry is adaptedto compare said measurement to said rehabilitation information.

In an exemplary embodiment of the invention, said circuitry is adaptedto compare rehabilitation improvements of said patient to trends in saidrehabilitation information.

In an exemplary embodiment of the invention, said circuitry is adaptedto change at least one motion parameter responsive to said measurement.Optionally, said change is within a time frame of said movement.

In an exemplary embodiment of the invention, said circuitry is adaptedto detect an intent to move of said patient and provide control of saidmovement element in response thereto.

In an exemplary embodiment of the invention, said circuitry is adaptedto detect a readiness to move and provide control of said movementelement in response thereto.

In an exemplary embodiment of the invention, said circuitry is adaptedto change a signal processing of said measurement responsive to adetection of movement or lack thereof.

In an exemplary embodiment of the invention, said brain monitorcomprises an EEG monitor.

In an exemplary embodiment of the invention, said brain monitorcomprises a blood flow measuring device.

In an exemplary embodiment of the invention, said brain monitorcomprises an fMRI system.

In an exemplary embodiment of the invention, said movement elementcomprises a robotic manipulator.

In an exemplary embodiment of the invention, said movement elementcomprises a resistive movement element which resists motion in acontrollable manner.

In an exemplary embodiment of the invention, said movement element isadapted to be capable of substantially unrestricted movement in 3D spaceover a volume of at least 30 cm in minimum dimension.

In an exemplary embodiment of the invention, said movement element isadapted to be selectively coupled and decoupled to at least one type ofbody portion.

In an exemplary embodiment of the invention, said circuitry is adaptedto provide cognitive rehabilitation to said patient.

In an exemplary embodiment of the invention, said circuitry comprises amemory which stores a rehabilitation progress of said patient.

In an exemplary embodiment of the invention, the device comprises atleast two movement elements which said circuitry is configured toidentify as being associated with opposite limbs.

There is also provided in accordance with an exemplary embodiment of theinvention, a method of rehabilitation, comprising:

controlling the motion of at least part of a patient as part of arehabilitation process; and

measuring brain activity of said patient, in association with saidcontrolling.

Optionally, the method comprises:

(a) deciding on a desired brain rehabilitation; and

(b) controlling said motion to effect said rehabilitation.

Optionally, said desired rehabilitation comprises corticalreorganization.

In an exemplary embodiment of the invention, the method comprisesdiagnosing the patient based on said measuring. Optionally, diagnosingcomprises controlling said motion to achieve a plurality of desiredmotions for said diagnosis. Alternatively or additionally, diagnosingcomprises generating at least an indication of brain plasticity for saidpatient.

In an exemplary embodiment of the invention, the method comprisescontrolling said motion in response to said measuring.

In an exemplary embodiment of the invention, the method comprisescontrolling said measuring in response to said motion.

In an exemplary embodiment of the invention, the method comprisesmeasuring during said motion.

In an exemplary embodiment of the invention, the method comprisesrepeating said controlling and said measuring for a same motion at least10 times.

In an exemplary embodiment of the invention, the method comprisesrepeating said controlling and said measuring for at least 20 differentmotions in a same day of rehabilitation.

In an exemplary embodiment of the invention, the method comprisescomparing measurements for a healthy side and a paretic side.

In an exemplary embodiment of the invention, the method comprisescomparing movements for a healthy side and a paretic side.

In an exemplary embodiment of the invention, the method comprisesmeasuring said motion.

In an exemplary embodiment of the invention, the method comprisesmeasuring a quality of said motion.

In an exemplary embodiment of the invention, the method comprisestracking a progress of said rehabilitation process of said patient basedon said measurements.

In an exemplary embodiment of the invention, the method comprisestraining a patient to control cortical activity using said controllingof motion as feedback.

There is also provided in accordance with an exemplary embodiment of theinvention, a method of treatment targeting, comprising:

a patient locally activating a brain region; and

applying treatment to said brain region in synchrony to said activation.

Optionally, applying treatment comprises physical rehabilitation whichuses said brain region.

Optionally, applying treatment comprises delivering a drug.

In an exemplary embodiment of the invention, stimulating said brainregion using external means that directly stimulate brain tissue.

In an exemplary embodiment of the invention, said locally activatingcomprises forcing a patient to locally activate a region using aphysical exercise.

In an exemplary embodiment of the invention, said locally activatingcomprises detecting local activation of said region.

There is also provided in accordance with an exemplary embodiment of theinvention, a method of brain monitoring, comprising:

generating brain activity by at least guiding a patient to at leastintend to carry out a known physical activity;

first monitoring brain activity using a first brain monitor;

second monitoring said activity using a second brain monitor of adifferent type;

determining a correspondence between results of said first and saidsecond monitoring;

performing rehabilitation on said patient using said second monitor; and

assessing a brain activity of said patient during said performingutilizing a correspondence between said first monitoring and said secondmonitoring.

Optionally, said assessing comprises assuming a fixed relationshipbetween said results.

Optionally, said generating comprises generating under computer control.

Optionally, said generating comprises repeating a same at least intentat least 10 times.

Optionally, said second monitoring comprises electrical monitoring.

Optionally, said second monitoring is significantly lower cost than saidfirst monitoring.

Optionally, said first monitoring comprises fMRI.

There is also provided in accordance with an exemplary embodiment of theinvention, a method of rehabilitation comprising:

(a) reorganizing brain functions; and

(b) after said reorganizing rehabilitating motor control utilizing saidreorganizing.

Optionally, said reorganization comprises reorganizing using a physicalmanipulation system to provide feedback to a patient.

There is also provided in accordance with an exemplary embodiment of theinvention, a method of controlling rehabilitation, comprising:

defining a desired dosage of a rehabilitation for a patient, whereinsaid dosage is defined as a function of patient activity;

monitoring the application of said dosage to the patient using acomputerized rehabilitation system.

Optionally, said dosage comprises a dosage of physical exertion.

Optionally, said dosage comprises a dosage of mental exertion.

Optionally, said dosage comprises a dosage of attention.

Optionally, said dosage is defined per a brain region.

There is also provided in accordance with an exemplary embodiment of theinvention, a method of measuring brain patterns, comprising:

providing repeated movement exercises of a patient, under computercontrol; and

collecting measurements of brain activity from said repeated movements;and

analyzing said measurements to yield a more precise measurement of brainactivity in response to the movement.

Optionally, the method comprises filtering out bad measurements.

In an exemplary embodiment of the invention, the method comprisesprogramming a BCI using said more precise measurement.

In an exemplary embodiment of the invention, the method comprisesanalyzing said more precise measurement to diagnose said patient.

In an exemplary embodiment of the invention, said diagnosis comprises aquality of brain activity.

In an exemplary embodiment of the invention, said diagnosis comprisesbrain plasticity.

In an exemplary embodiment of the invention, the method comprisesanalyzing said more precise measurement to close a loop in arehabilitation process.

There is also provided in accordance with an exemplary embodiment of theinvention, a method of rehabilitation, comprising:

instructing a person to carry out certain movements while being coupledto a spatial manipulator; and

instructing said spatial manipulator to guide said person to perform anincorrect motion.

Optionally, the method comprises defining a rotational or translationalmapping between said movements and said incorrect movements.

In an exemplary embodiment of the invention, the method comprisesmeasuring a cortical response to said person detecting said incorrectmotion.

There is also provided in accordance with an exemplary embodiment of theinvention, a method of ensuring mental imagery, comprising:

providing instructions to a patient to guide a mental imagery thereof;

measuring movement of a patient in response to said imagery;

comparing said instruction to said motion; and

providing feedback to said patient regarding said imagery.

Optionally, the method comprises measuring brain activity correspondingto said imagery.

Optionally, the method comprises comparing said brain activity to brainactivity collected during said motion.

In an exemplary embodiment of the invention, the method compriseschanging said instruction to prevent habitation of said patient.

In an exemplary embodiment of the invention, said instructions comprisesinstructions while said patient has closed eyes.

BRIEF DESCRIPTION OF THE FIGURES

Particular embodiments of the invention will be described with referenceto the following description of exemplary embodiments in conjunctionwith the figures, wherein identical structures, elements or parts whichappear in more than one figure are optionally labeled with a same orsimilar number in all the figures in which they appear, in which:

FIG. 1 presents an averaged Motor Related Potential template thatillustrates BP periods;

FIG. 2 shows a typical event-related potential in an S1-S2 paradigm,measured from central derivations;

FIGS. 3-5 show temporal and topographic distributions of BP amplitudesover the entire scalp surface, for different types of motion;

FIG. 6A shows an exemplary rehabilitation system in accordance with anexemplary embodiment of the invention;

FIG. 6B shows a proposed recording arrangement to monitor MAC and theexpected signals, in accordance with an exemplary embodiment of theinvention;

FIG. 7 is a flowchart of a method of recording bilateral corticalactivation, in accordance with an exemplary embodiment of the invention;

FIG. 8 shows SCP signals measured from a patient;

FIG. 9 shows mu rhythm sensing used to control a target;

FIG. 10 is a flow chart of a process of agonist/antagonistrehabilitation, in accordance with an exemplary embodiment of theinvention; and

FIG. 11 is a flowchart of a method of initiating motion, in accordancewith an exemplary embodiment of the invention.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS Overview

Many embodiments of the present invention focus on methods ofrehabilitation. First, an exemplary system which may be useful for themethods is described and then various methods and methodologies aredescribed. In an exemplary embodiment of the invention, the methodsand/or methodologies are implemented as software on a rehabilitationsystem. In some embodiments however, the methods may be partly manualand/or implemented in a distributed manner.

Exemplary System

FIG. 6A shows an exemplary rehabilitation system/device 600 inaccordance with an exemplary embodiment of the invention. System 600includes a robotic actuator or other actuator device 602 which includesa limb manipulator 604, for example, for moving an upper limb 606.Manipulator 604 optionally manipulates only a single point on a limb. Inother embodiments, multiple limbs (or other body parts) and/or multiplepoints on a limb (e.g., joints) are manipulated. Alternatively oradditionally to manipulation, manipulator 604 is used to measuremovement of a limb and/or provide kinesthetic feedback to a user. Patentapplications which describe exemplary such manipulators are providedbelow. Optionally, the manipulator comprises an articulated arm or otherrobotic affector.

In some methodologies in accordance with exemplary embodiments of theinvention, work is performed (e.g., by attachment to system 600) on asingle arm at a time; sometimes both arms are exercised together in amirror-like fashion and sometimes the arms are exercised alternativelyone after the other.

A particular intention of some embodiments of the invention is tointeract with the cerebral aspects of rehabilitation, as they relate,for example, to the plasticity and/or training of a brain 608. In anexemplary embodiment of the invention, brain 608 is damaged due totraumatic brain injury or a stroke. There may also be physicaldisabilities, for example arthritis (or damage otherwise unrelated toinjury) or orthopedic damage (e.g., related to injury). In some cases,rehabilitation is limited by physical disability and/or is modified sothat the patient learns motion control that is appropriate for hisphysical limitations (e.g., using a cane or walker may suggest differentcognitive goals than regular walking, for example, with regard toresponse time).

In some exemplary embodiments of the invention, various measurements 613of brain function, for example, SCP 610, MAC 612 and/or Mu rhythm 614are collected. Other measurements, for example, physiologicalmeasurements 611 may be collected as well. A controller and/or softwaremodule 616 is used to process and/or monitor central (brain) activity.In various configurations this and/or other modules may be separate,local, remote and/or implemented in various manners, such as hardwareand/or software, centralized and/or distributed. In an exemplaryembodiment of the invention, the controller includes a memory withrehabilitation information and/or programming thereon. Optionally, therehabilitation information includes one or more of: a diagnosis, arehabilitation plan, progress reports, rehabilitation mile stones,templates of expected progress, diagnosis templates, exercise plans(e.g., motion parameters) and/or recordings of sessions.

Alternatively or additionally to surface EEG measurements, othermeasurement means may be used, for example, fMRI, high resolution EEG,Hemato Encephalography (HEG), evoked potentials, implanted electrodes(wired or wireless), PET scanning, NM imaging and/or other brain and/orfunctional imaging and/or measurement methods known in the art. In anexemplary embodiment of the invention, multiple brain measurementmethods are used, for example, EEG for during exercises and fMRIperiodically, for example to assess improvement and/or to correlate withthe EEG. In some cases, even expensive imaging methods, like fMRI may beused during a rehabilitation session, for example, to assess plasticity.In addition it should be noted that brain measurement serves differentpurposes in different embodiments, for example, in some embodiments,brain measurement is used to determine when an intention to act exists(which may require a high temporal resolution), in some whether changesin general activation levels are found (which may benefit from higherspatial resolution) and/or in others, for assessing an on-going changein ability.

Optionally, measurement of EMG is performed, for example using amulti-channel sEMG recording device 618, on a healthy and/or pareticlimb. A monitor/module 620 is optionally provided for monitoring therecordings. In an exemplary embodiment of the invention, sEMG recordingsare correlated with brain measurement signals and/or mechanical outputof the patient.

Optionally, a functional stimulator 622 is provided, to providesub-threshold and/or above threshold stimulation of muscles and/ornerves, in association with sEMG measurement and/or other rehabilitationprocedures. In an exemplary embodiment of the invention, the stimulationis provided as a sequence of stimulations of one or more muscle groups,for example in synchronization to a time clock or in response (e.g.,and/or delay) to a trigger. Optionally, the stimulation is electrical ormagnetic stimulation.

In an exemplary embodiment of the invention, one or more implantedstimulators (wired or wireless) is used. Optionally, such stimulatorsare used for measuring EMG in addition or instead of being used forstimulation.

Wireless implantable electronic stimulators have been described, forexample in: U.S. Pat. No. 5,193,539, U.S. Pat. No. 5,193,540, U.S. Pat.No. 5,312,439, U.S. Pat. No. 5,324,316, U.S. Pat. No. 5,405,367, PCTPublication WO 98/37926, PCT WO 98/43700, PCT Publication, WO 98/43701Oct. 8, 1998, U.S. Pat. No. 6,051,017, U.S. application Ser. No.09/077,662 and in an article “Micromodular Implants to ProvideElectrical Stimulation of Paralyzed Muscles and Limbs”, by Cameron, etal., published in IEEE Transactions on Biomedical Engineering, Vol. 44,No. 9, pages 781-790. The disclosures of all of these references areincorporated herein by reference.

In an exemplary embodiment of the invention, a mechanical performancemonitor module/software 624 is provided, for example, for assessingquality of motion and/or other motion parameters. Optionally, the actualmotion is compared to planned motion.

Optionally, a camera 615 is provided. A camera may be used, for example,to provide feedback to a patient, to acquire and capture images whichcan be analyzed to determine quality of motion, for assistinginteraction with a remote or a local therapist (who has only one pair ofeyes) and/or to generate cuing movies for indicating motions to apatient. In some embodiments of the invention a camera and/or a positionsensor are used to detect patient motion instead of using a manipulator.

A central controller (not specifically shown outside of device 602) isoptionally used for planning, monitoring and/or providing some or all ofthe functions described above. Feedback to a user is optionallyprovided, for example as a visual display (628) or as audio and/ortactile feedback. Optionally, music (e.g., rhythmic sounds) is used forfeedback and/or guiding the patient and/or therapist. A mechanicalprocessing and storage module 626 is optionally provided as a separatemodule or as a portion of the central controller.

Optionally, a triggering facility is provided, for example being usedfor summation and/or averaging of signals. This is optionally used tofilter noise and increase signal/noise ratio (for example to providesynchronized evoked potentials or to measure complex signal in responseto a structured behavioral algorithm as in Contingent Negative Variation(CNV)). Optionally, the mechanical ability of actuator 602 is used toensure repeatability between measurements.

Optionally, a brain stimulation tool (STM) 630 is provided, for example,utilizing one or more of implanted electrodes, external electrodes,drugs, targeted drug delivery and/or magnetic or heat stimulation.Optionally, selective activation of brain areas in conjunction withtimed (optionally automatic and/or triggered) delivery of drugs is usedto enhance delivery of drugs to active areas. Optionally, a persons'ability to control SCP (described below) is made use of for variousapplications, for example, activating (or deactivating) areas ofinterest in the cortex. Optionally, STM 630 is used in conjunction withactivation caused by rehabilitation activities and/or patient control.Optionally, such conjunction is used for timing and/or parameter controlof one or more of stimulation, drug provision and rehabilitationexercises.

In an exemplary embodiment of the invention, targeted activation (e.g.,using stimulators, rehabilitation and/or patient control) of brain areasis used for other types of therapy, such as enhancing effect of drugs inthe active area (by virtue of its being active or by virtue of increasedblood flow) and guiding the integration of implanted tissue, forexample, implanted stem cells or allograft tissue. Optionally, guidingof growth of existing nerve cells is targeted using methods describedherein.

Optionally, device 600 includes a means, such as circuitry for timing aprovision of the drugs to the activation.

Optionally, a therapist display 617 is provided, for example for showinginstruction and/or feedback to a therapist. This display may be remote,for example.

Optionally, a virtual reality (VR) system 619 is provided, for exampleincluding one or more of visual goggles, a panoramic display, 3D sound,tactile sensors and/or tactile feedback.

Optionally, the VR system is used to better emulate real-worldsituations a patient is to be rehabilitated for. Optionally, the VRsystem is used to enhance reality, for example by showing a desiredmotion overlaid on a view of the patient showing his limbs actuallymoving. Optionally, a standard display is used, in which a capturedvideo stream is enhanced.

In an exemplary embodiment of the invention, the therapy is provided toa patient using virtual reality as a tool for interacting with thepatient. Optionally, a test is made to determine which virtual realitysetting has a most calming effect on a patient or otherwise interactsfavorably with the rehabilitation process. Optionally, EEG or otherbrain measurements are used to determine the effect on the patient.

A device utilizing robot manipulation with MAC and methodology isoptionally applied in various different ways depending on the degree ofparesis and the purpose of the exercise.

The complexity of motion may vary. For example, sometimes a singlemovement is repeated again and again and in others, two or moremovements (or a more complex schedule) is repeated. In some cases aschedule is established, for example, an “easy” movement is followed bya “difficult” one to encourage further plasticity after somerehabilitation gain has been established.

In an exemplary embodiment of the invention, system 600 is used as aspecific motion inducement trainer. Instead of conventional “ConstrainedInduced Therapy” for hemi paresis, system 600 can be used as a dynamicalternative by facilitating schedules programmed by the professionaltherapist with a deep knowledge of the particular neurologicallimitations of the patient. Relevant trajectories with a particularlevel of resistance are optionally encouraged or allowed.

In an exemplary embodiment of the invention, system 600 is used toprovide a personalized level of training Optionally, a positive feedbackloop is established between the mechanical and neurological modules ofsystem 600 so that the degree of complexity of the movements exercisedby the former matches the performance recorded by the later. Forexample, the higher the recorded central activation the bigger the forceneeded to move manipulator 604 over a very well known movement loop.This type of feature can provide improvements during the later stages ofthe rehabilitation process, when progress can be most difficult. Thistype of interaction may allow the patient to “specialize” in certainparts of the movement while being less challenged during parts overwhich the patient does not have enough control. In an exemplaryembodiment of the invention, this type of feedback allows a patient tobe treated according to his therapeutic level. In an exemplaryembodiment of the invention, the system assists a user in initiating amotion (e.g., by continuing it once started) or in completing a motion(e.g., by stopping at the end, optionally with a gradual slow-down).Optionally, measurement of the ability of the patient to initiate,carry-through and/or stop a motion are used as indicators ofrehabilitation progression.

In an exemplary embodiment of the invention, movement comprises one ormore of passive active and intermediate and other movement types. A listof particular exemplary motions is described further below. It is notedthat in some cases, certain movements may not be appropriate, forexample a paretic patient who is totally immobile cannot be expected tomove against resistance.

Optionally, music and/or rhythmic sounds are used as part of therehabilitation process. In an exemplary embodiment of the invention,integrated uses of music rhythm and lighting are used to enhancefeedback linkage and/or to add an entertainment dimension to therehabilitation process. For example, bongo tapping is a generallyuplifting activity. It is possible that this may be due to the rhythmichypnotic reward provided by the sound linked to the repetitivecoordinated movement. In an exemplary embodiment of the invention, it isconsidered that multi-sensorial linked performance tends to promotephysiological and cortical coherence and system 600 is used to promotesuch coherence by providing multiple feedback modes and/or activation ina rhythmic manner which may assist in rehabilitation.

Previous Patent Applications

The following is a table of patent applications sharing applicantsand/or inventors with the present application and which provide variousapparatus and methods possibly helpful for carrying out embodiments ofthe present invention.

Title Serial_# Filing Date Exemplary contents Methods andPCT/IL2005/000142 Feb. 4, 2005 Describes various methods and Apparatusfor apparatus for rehabilitation, including Rehabilitation manipulatorsand methods of taking and Training motivation into account. Methods andPCT/IL2005/000136 Feb. 4, 2005 Describes method and apparatus forApparatuses rehabilitating while sitting and/or for rehabilitatingbalance and coordinated Rehabilitation movements. Exercise and TrainingGait PCT/IL2005/000138 Feb. 4, 2005 Describes method and apparatus forRehabilitation rehabilitating gait and other multi-joint Methods andand/or coordinated movements. Apparatuses RehabilitationPCT/IL2005/000137 Feb. 4, 2005 Describes using music as feedback andwith Music for guiding rehabilitation. Neuromuscular PCT/IL2005/000135Feb. 4, 2005 Describes using sEMG and FES as part Stimulation of arehabilitation process. Fine Motor PCT/IL2005/000139 Feb. 4, 2005Describes devices and methods for Control rehabilitating fine motorcontrol, such Rehabilitation as writing. Neuromuscular PCT/IL2005/000442Apr. 28, 2005 Describes methods and apparatus for Stimulationrehabilitating using implanted wireless electrodes. Motor 60/686,991Jun. 2, 2005 Describes methods and apparatus that Training with relateto rehabilitation while monitoring Brain Plasticity a brain Device and60/665,886 Mar. 28, 2005 Describes rehabilitation and/or support Methodfor devices suitable for persons of limited Training, mobilityRehabilitation and/or Support Apparatuses 60/666,136 Mar. 29, 2005Describes retrofitting exercise device for Retrofitting for use inrehabilitation Exercise Equipment and Methods for Using Same Methods andUS filing. Attorney Aug. 18, 2005 Describes methods and apparatus forApparatuses docket 414/04572 rehabilitation for Rehabilitation andTraining

The disclosure of all of these applications are incorporated herein byreference. In general, the techniques and apparatus in these patentapplications can be used for providing rehabilitation of various bodyparts and/or feedback and/or be used in conjunction with cerebralmonitoring as described herein.

Overview and Exemplary Uses of System 600

There are many ways in which a system such as system 600 can be used forrehabilitation in conjunction with cognitive rehabilitation and/orcognitive assessment. The following provides a sampling of such uses,with some particular exemplary uses being described after with exemplaryprotocols of application.

A first group of uses relates to robot-assisted rehabilitation whichutilizes EEG or other assessment of brain activity. In an exemplaryembodiment of the invention, the assessment is used to induce and/ormeasure brain plasticity. In an exemplary embodiment of the invention,brain and manipulator function are correlated or interact, for example,using one to trigger or generate the other.

In an exemplary embodiment of the invention, measurements of brainactivity are used to provide feedback to one or more of patient, systemand/or therapist, for example, during an exercise, during a sessionand/or between sessions. In an exemplary embodiment of the invention,the cortical effect of a rehabilitation exercise is thus assessed and/oroptionally correlated with physical effect of the rehabilitation. Thismay be used to identify problems in the rehabilitation process and/orpatient limitations. In an exemplary embodiment of the invention, thefeedback is used for more cortically specific rehabilitation, in whichrehabilitation exercises and/or parameters are used to selectively focuson certain brain areas and/or restructuring methodologies. Optionally,an exercise is used if it shows a desired selective, cortical and/orrestructuring effect. The exercise is optionally dropped, reduced inimportance or its parameters changed, if a desired effect is not found.It is noted that a particular benefit of intra-session analysis is afast response to patient needs. Optionally, feedback that changes anexercise is provided in less than 30 minutes, less than 10 minutes, lessthan 5 minutes, less than one minute, less than 30 seconds or smaller orintermediate times.

In an exemplary embodiment of the invention, the rehabilitation is usedto effect an improvement effect on motion and/or on a desire to carryout a motion.

In one exemplary embodiment of the invention, the bilateral ReadinessPotential is monitored, quantified and/or displayed prior to a precisemovement path (e.g., provided by a robot), in order to induce, monitor,entrain and/or assess plastic changes in the brain.

In an exemplary embodiment of the invention, rehabilitation is based onthe assumption that when there is a temporal and/or physiologicallinkage between the planning of a movement, the subsequent execution ofthat movement by a paretic arm, the kinesthetic perception of such amovement via sensorial fibers that may be intact, the actual witnessingof the movement taking place at a physiologically expected time afterthe resolution to start it, and/or the possibility to accurately returnto all the above steps repeatedly with the help of a specializedphysiologically based rehabilitation manipulator on the one hand and/orthe possibility of enhanced and facilitated positive plastic change onthe other hand. Not all these items need be correlated in order to havea beneficial effect. In an exemplary embodiment of the invention, anaccuracy required of the patient during a rehabilitation session (e.g.,to define matching) is selected to be suitable for the task. Forexample, an accuracy and/or repeatability of better than 5 cm, 3 cm, 1cm, 0.5 cm or better may be required for different tasks.

In an exemplary embodiment of the invention, a robotic manipulator, forexample an apparatus as described in U.S. provisional application60/542,022, the disclosure of which is incorporated herein by reference,is used. This apparatus can include an optional display, an optionalprocessor, an optional user input and a robotic manipulation portion ora resistive portion. In some embodiments described therein, the devicecan be configured for one or more of causing a set motion, resistingmotion, copying motion between limbs (e.g., hands, arms, feet or legs),assisting motion of a limb and performing motion of multiple joints. Inaddition, such a manipulator can also measure limb positions and forcesor these can be measured in other ways. The use of a processor and aninput can allow more detailed programming. In an exemplary embodiment ofthe invention, the programming includes exact repetition and processingof physiological signals in a manner that matches the repetition.

While a robotic manipulator is not strictly required, a potentialadvantage of some such manipulators is the ability of the manipulator tomeasure, repeat and modify in a very controlled way a wide range ofmovements. Controlled features of the robot optionally include one ormore of kinetic, positional and temporal variables such as path,velocity strength acceleration, repetition rate and/or synchronizationto brain rhythms.

Various methods are optionally used to assess brain function, forexample, one or more of fMRI, EEG, HEG, implanted electrodes and othermethods known in the art. Optionally, a lower cost method such as EEG isused during rehabilitation, even though its resolution may be lower.Optionally, calibration is carried out, for example at a start ofrehabilitation and/or periodically, to generate a correspondence betweena high resolution method and a low resolution method. In one example, anfMRI is calibrated to EEG, by the patient being instructed (e.g., by atherapist and/or an apparatus) until a desired motion or cognitiveeffect is achieved. That a correct or known effect is achieved may bedetermined by the fMRI system. During rehabilitation it may be assumedthat if a corresponding EEG signal is achieved, this means that theunderlying cognitive effect as viewed on the fMRI signal is also beingachieved, at least in approximation. Optionally, calibration is repeatedwhen a new effect is being trained or if it is felt that the EEG (orother lower quality signal) is not generating a correct indication.

In an exemplary embodiment of the invention, the method used formeasuring brain activity is a nIR Mass Spectrometry orSpectrophotometry, a non invasive non-contact method of monitoringOxygen levels (e.g., Oxy-Deoxy Hemoglobin) or other metabolic and/orfunctional markers at brain cortex via optical means. In an exemplaryembodiment of the invention, nIR Mass Spectrometry sensors (optionallybased in “optodes”) are positioned over the motor cortex (or other partsof the scalp or inside the skull) and compare normal with paretic sidesignals while the patient performs exercises. An article describing sucha system is “On-line optical imaging of the human brain with 160-mstemporal resolution” by Maria Angela Franceschini et al. 31 Jan.2000/Vol. 6, No. 3/OPTICS EXPRESS 49, the disclosure of which isincorporated herein by reference.

In an exemplary embodiment of the invention, use is made of acorrelation between periodicy in brain function and periodicy in motorcontrol. In an exemplary embodiment of the invention, a task is providedwhich has an intrinsic frequency. This frequency is used as a filter forfiltering EEG signals for better detecting signal sources and/orcharacteristics. Alternatively or additionally, the rhythm in the brainis detected and a motor activity is modified to match that rhythm.Optionally, a test is made to determine, for that particular patient,which brain rhythms are easier to maintain. Optionally, a plasticitymeasure of brain function is derived from the ease in which a brainrhythm is changed by changing an underlying task. It is expected that aless plastic brain will be able to follow such changes more slowlyand/or fail in an exercise faster than a more plastic brain.

Additional apparatus useful in the practice of the invention isdescribed in U.S. provisional application 60/566,078, the disclosure ofwhich is incorporated herein by reference, in which EMG measurement in ahealthy limb is used for controlling the rehabilitation and/orstimulation of an unhealthy limb. There are optionally four EMGchannels, one channel measuring EMG signals from each of four muscles:the biceps, the triceps, the flexors, and the extensors. Each channeluses three electrodes, two recording signals from near each end of themuscle, and one reference electrode in the middle. In that application,a low level signal based on the measured EMG in the healthy limb wasapplied to the paretic limb, to assist in motion, to provide feedback tothe patient and/or to provide encouragement.

In an exemplary embodiment of the invention, the capabilities of a robotmanipulator for movement planning, programming, precise repetition,and/or an optional high degree of synchronization with the MACmonitoring, allow for complete or more complete control over one or moreimportant factors relating with rehabilitation.

In an exemplary embodiment of the invention, rehabilitation is based onthe assumption that a common characteristic of endogenous components(based on an internal assessment process) is the dependence onattention. Whereas exogenous components tend to persist under varyingdegrees of attentiveness towards the event, an endogenous event is oftenaugmented under increased attention or extinguished in the presence ofdistracting stimuli. Optionally, a measurement of the depth of CNV or BPcan reflect the attentive strength during rehabilitation.

In an exemplary embodiment of the invention, the apparatus providesvarious repetitive synchronized schedules of motion, which are used tomonitor and/or improve cortical activation associated with the motion.

In an exemplary embodiment of the invention, the apparatus is used toquantify and/or assess progress of cortical activation skill for exampleas associated with a repeatable movement schedule.

In an exemplary embodiment of the invention, the apparatus is used togenerally activate cortical networks previously dormant.

In an exemplary embodiment of the invention, the apparatus is used topromote synchronization between cortical activation and its associatedperipheral result, possibly reconciling motor output with sensoryfeedback.

In an exemplary embodiment of the invention, the apparatus is used toassess rehabilitation progress as practically related to improvement incortical activation and, (possibly indirectly), plastic redistributionand progress.

In an exemplary embodiment of the invention, one or more different typesof motion (e.g., Free, Synchronized, Syncopated) are tried with apatient and their relative effectiveness for rehabilitation (e.g., onthe basis of the degree of cortical activation related with each one ofthem), are estimated. Optionally, the rate of progression insynchronization of activation and/or in other parameters of corticalactivities (e.g., as compared to healthy subjects or motion of healthylimbs), is used to estimate rehabilitation time and/or expectedmilestones.

In an exemplary embodiment of the invention, one or more templates ofprogression of cortical activity and/or their association with physicalrehabilitation are stored and compared to actual progress of a patient.Optionally, a classification of the rehabilitation type is providedbased on the type of progress and/or interaction between robotmanipulation and cortical activity. Such classification can be asub-classification of a basic classification based on brain damage.Optionally, the templates are generated as plans for a patient.

In an exemplary embodiment of the invention, the detection of repeatedsignals is used to indicate that a correct brain activity is takingplace.

In an exemplary embodiment of the invention, an apparatus is used forproviding multiple ways of activating a motor pathway, including one ormore of: from higher brain centers (planning), from lower brain centers(feedback of forced motion) and/or from lateral brain center (copying ofmotion of laterally opposite limb). In an exemplary embodiment of theinvention, such multiple ways of activating may serve to assist apatient in overcoming a disability and/or discovering alternativepathways.

In an exemplary embodiment of the invention, rehabilitation is carriedout based on the assumption that when there is a temporal andphysiological linkage between the planning of a movement (BP), thesubsequent execution of that movement by a paretic arm (even when such amovement is largely or completely generated artificially, e.g. using arobot or by the sEMGs of muscles of the contra-lateral arm), thekinesthetic perception of such a movement via sensorial fibers that maybe intact, the actual witnessing of the movement taking place at thephysiologically expected time after the resolution to start it, and/orthe possibility to accurately return to all the above steps repeatedly(e.g., with a robotic manipulator); the possibility of positive plasticchange to recover mobility is facilitated and/or enhanced. Alternativelyor additionally, the above is used for testing and/or assessment.

In an exemplary embodiment of the invention, rehabilitation is carriedout based on the assumption that that combined peripheral nerve andbrain stimulation (“dual stimulation”) induces changes, for example ofexcitability of normal motor cortex. Alternatively or additionally,rehabilitation is carried out based on the assumption that “dualstimulation” induces motor cortex plasticity and associated functionalimprovements. Some basis for this may be found in (Uy J, Ridding M C,Hillier S, Thompson P D, Miles T S.: “Does induction of plastic changein motor cortex improve leg function after stroke?” Neurology. 2003 Oct.14; 61(7):982-4.), the disclosure of which is incorporated herein byreference.

In an exemplary embodiment of the invention, a robot manipulatorprovides a cuing structure (e.g., controlled vibrator) to mimic thesyncopate condition described above.

In an exemplary embodiment of the invention, readiness is assessed. Inan exemplary embodiment of the invention, a patient uses a manual inputto indicate readiness for an exercise (e.g., that planning iscompleted). In an alternative embodiment, brain activity analysis isused for such assessment. In one example, imposed motion is applied at atime when the patient is ready for it. In one example, brain signalprocessing indicates such readiness, as described in the background. Inanother example, various delays relative to such calculated readinessare tried out for a patient and/or for various types of motion. Inanother example, brain signal analysis is used to assess when thepatient's attention is properly focused. Optionally, such analysis isused as feedback for training the patient in improving his attentionand/or to assist a patient in detecting when such attention is lacking

In an exemplary embodiment of the invention, in addition to or insteadof contra lateral stimulation of muscles in a paretic arm, MAC slowwaves recorded as a result of well defined movement procedure (e.g.,organized and delivered by a robot manipulator) are optionally used asmarkers of attention and optionally as used to indicate or generated toact as promoters of plasticity and/or rehabilitation.

In an exemplary embodiment of the invention, intent is promoted and/ormeasured. In an exemplary embodiment of the invention, recording centralactivation (e.g., SCP, MAC) in sync with external movement gives aqualitative and/or quantitative assessment of degree of “intention” toperform a particular movement by the patient, which intention measuremay be used to promote plasticity and rehabilitation, for example, bytaking the existence of an intention as a starting point to actuallycarry out motion, as described in more detail below. Optionally, theassessment is carried out even when there is no muscular contractionexternalization. This is optionally accomplished by measuring (a)residual EMG without contraction; (b) brain activation overcontra-lateral somato-motor cortex; (c) general cortical activation asmeasured by central slow cortical potential; and/or (d) comparing slowcortical bilateral activation of paretic and normal side.

In an exemplary embodiment of the invention, “intention related signals”are rewarded (e.g., used for promotion), for example, by stimulating, asa response, the desired muscle on the paretic side through FES. In anexemplary embodiment of the invention, the amplitude of generalizedbrain activation is used to promote increasing FES stimulation of theparetic muscle. Possibly, through repetition of the same stimulation andresponse the brain “realizes” the link between a particular type ofbrain activation of an area previously lethargic and the preciseperipheral motor activity induced by the system. Returning to the samelinkage repeatedly may result in more plasticity.

In an exemplary embodiment of the invention, encouragement is providedduring rehabilitation, for example, indicating one or both of correct(or progressive) brain activity and motion. Optionally, provision of apower boost to an existing weak motion and/or augmenting positionalfeedback and/or reducing the complexity of motion can be used toencourage a patient additionally or alternatively to them being used toassist in the cognitive aspects of rehabilitation.

In an exemplary embodiment of the invention, cortical signal movementsignatures are used. In an exemplary embodiment of the invention, thecortical signals of a population of “movement professionals” such asdancers or Tai Chi practitioners is measured, for example using amanipulator in association with neural electrodes and/or imaging.Optionally, the manipulator is used to measure force information and/ormeasure behavior when encountering resistance and/or spatial asymmetry(e.g., standing crooked). Optionally, a patient is trained to generatematching signals (e.g., using methods as described herein) or thesignals are used as triggers for applying FES to the patient.Alternatively to movement professionals, a signature of the patienthimself (e.g., from before brain damage or from healthy limb) are used.

A set of uses of some embodiments of the invention relates to using arobotic manipulation system (e.g., active or passive) for diagnosis. Inan exemplary embodiment of the invention, the system is used to performdifferent manipulations and/or complexity levels in a way which will(should) either cause expected brain activation patterns or require theuse of certain brain areas. For example, asking a patient to repeat acomplex motion exemplified by the system will activate brain areasdifferently from asking a patient to maintain a constant velocity ofmotion in a circle under a condition of varying resistance. In anotherexample, more complex motions may require a greater planning effort.

In an exemplary embodiment of the invention, a robotic system is used inassessment of plasticity and/or progress and/or efficacy of arehabilitation treatment. In an exemplary embodiment of the invention,the system provides a same set of repeated exercises, for example,repeated during a same session (to assess intra-session improvement andprovide one measure of brain plasticity, based on improvement in one ormore of cortical activity and/or motor ability) or in different sessions(to assess progress between sessions).

It should be noted that a controlled system can optionally control oneor more of: the required motion, measurement of variations, timing,graduated changes and/or provide variations in order of exercises. Someof these features may be available using manual methods. However, it isbelieved that in many cases there is too large a variability to allowpurely manual application of testing exercise to be as effective asmachine applied and machine assisted exercises. Optionally, a machinecan provide repeatability to within better than 10%, 5%, 1% orintermediate or better values for desired timing, position and/orforces, as compared to the actual carried out action. Optionally,improvement of central recordings (for example MAC) over apre-established and repeatable movement loop are recorded and quantifiedas an indirect qualitative assessment of plastic enhancement. In someembodiments of the invention, rehabilitation is based on the assumptionthat repetition of defective movements brings about plastic enhancement,which is thus practiced, e.g., a patient is asked to repeat the bestmotion he is capable of to enhance plasticity instead of requiringimproved quality towards a goal. Optionally, the plasticity is assessedduring such repetition to determine its effectiveness and/or decide howlong to continue. Optionally, instead of directly measuring plasticity,a negative measurement is made, in which what is looked for is a lack ofplasticity which was expected. For example, assuming 100 repetitionswill induce plasticity and measuring once a week or less often to see ifthere were plasticity changes (e.g., by brain imaging), can be used as amethod to track plasticity.

Optionally, temporal linkage between cortical activity and machinegenerated movement may also enhance plasticity in a different way(similar but possibly better than using a mirror image technique). Herethe actual movement of the paretic arm when expected by the brain,(activated by intention and audiovisual stimuli from the system) mayprovide an especially significant synchronized sensorial input thatinduces and catalyzes regaining of movement.

Optionally, by recording physiological signals and assessing movementimprovement of many individuals over long periods of time the systemsupports the comparing of intra- and inter-personal performance byrelating the performance of patients and comparing patient results to asuitably related population of plasticity “signatures”. Optionally, thiscomparison can be independent of the patient actual condition, forexample, independent of where the damage is in the brain. Alternatively,when the comparison is indexed to a damaged area and/or extent in thebrain, such a measure helps show the basic plasticity of the brainand/or possibly underlying motivational and/or cognitive problems.

In an exemplary embodiment of the invention, the effectiveness ofrehabilitation is assessed by detecting one or both of enhanced activityin one hemisphere when motion typically related to the other hemisphereis carried out, or by increased activity in a damaged hemisphere.

In an exemplary embodiment of the invention, brain activity is monitoredto determine if a physical rehabilitation activity is having a desiredeffect in the brain. In an exemplary embodiment of the invention, thebrain measurements are used as feedback to a patient (or a therapist ora controller) to indicate if the patient is applying a correctconcentration or directed effort. Failure by the patient may suggest theuse of other exercises. In one example, if it is clear that the patientis expending effort on a wrong activity, a new exercise where the wrongactivity is minimized (e.g., power boosting of motions) may be provided.In another example, complex exercises may be simplified to the pointwhere a patient is able to achieve correct (or progressing) brainactivation.

In an exemplary embodiment of the invention, monitoring of brainactivity is used to detect restoration of a correct balancing of brainactivation. In some cases, such balancing is not possible due to organicdamage. However, an expected degree of balancing (e.g., based on anassessment of damaged tissue) can be aimed for. In other cases, asimilar activation across a range of exercises is a target.

In an exemplary embodiment of the invention, the characteristics of themovement, (for instance free, synchronized or syncopated) and/or thepresence or absence of a pre-warning cue, (promoting a CNV type ofresponse), may determine the degree of contra-lateral spread of the MACsignal over the scalp. In an exemplary embodiment of the invention, thecharacteristic may be selected intentionally to have a desired effect.Alternatively or additionally, the brain activity may be measured todetermine if a desired effect was achieved.

In an exemplary embodiment of the invention, desired rehabilitation timeand/or type are assessed. In an exemplary embodiment of the invention, abaseline is set for one or both of motion ability and corticalelectrical activity. The performance of a patient is compared to one orboth baselines, for example to determine a rehabilitation stage,rehabilitation block (e.g., certain brain area not progressing) and/or aprogress rate. In an exemplary embodiment of the invention, the baselineis set by the same patient for a healthy limb. Alternatively oradditionally, the baseline is set by a healthy person. In an exemplaryembodiment of the invention, a patient is compared to progress andmeasurements of other patients with similar healthy brain scans (e.g.,for unimpaired motion) and/or patients with similar organic damage.

In an exemplary embodiment of the invention, diagnosis is carried out byhaving a patient try out a same motion with a healthy and a paretic arm.As the amplitude of CNV generally reflects preparation forcontra-lateral motor activity, this may provide a way to assessperformance of a damaged side (in case of hemi-paretic subject).Optionally, such diagnosis is continued during rehabilitation, forexample to establish and/or quantify the degree of recovery reached.

A set of uses of some embodiments of the invention relates to assistingcognitive rehabilitation using a robotic manipulation system.

In an exemplary embodiment of the invention, selective treatment ofbrain areas is provided. In an exemplary embodiment of the invention, amanipulation and measurement system optionally as described herein isused to identify the edge of a damaged area in the brain, so thatplasticity and rehabilitation efforts may focus on that area.Optionally, such an edge area is identified by its having a raggedactivation profile.

In an exemplary embodiment of the invention, local activation isprovided, for example, by one or more of heating, magnetic brainstimulation, electrical stimulation and/or drug delivery. In anexemplary embodiment of the invention, selective activation of therelevant brain area is provided by cognitive feedback training of thepatient to activate a brain area and then provision of a drug or othergeneralized treatment. Optionally, such selectively is applied before,during and/or after a physical rehabilitation exercise which addressesthat area. Optionally, the timing and/or relative triggering areprovided by a manipulator system which measures brain activity and/orphysical activity.

In an exemplary embodiment of the invention, a manipulation device isused for providing direct cortical rehabilitation. In an exemplaryembodiment of the invention, SCP signals recorded from a single point ofthe scalp, (for instance Cz), are used in a biofeedback fashion to teachthe patient to control the negativity (cortical activation) orpositivity (cortical deactivation) of the signal at that point. Once thepatient is able to control the SCP signal at a single point, one featureof the signal (for instance its negativity) is optionally used to drivea manipulator in space, for example, in a mono-directional fashion inone plane. Later, after further progress of the patient, optionally, thevarious features of the signal are translated into a binary code used todrive the manipulator in space in a mono-directional fashion in oneplane. Later after yet further progress, optionally, by measuring atvarious different points over the scalp, the patient is trained tocontrol the SCP signal at each one of them simultaneously and thatinformation is translated into binary codes used to teach the patient todrive the manipulator in space in a multidirectional fashion;optionally, first in a single plane and later in a three dimensionalmode. The manipulator may be used for one or both of producing amovement as a response to the particular combination of cortical signalsand/or enhance and amplifying traces of movement conquered by thepatient. Optionally, the patient is selectively instructed to try andcarry out motions and/or image the motions.

In an exemplary embodiment of the invention, at a later stage inrehabilitation after the patient learns to move the manipulator withhis/her SCP signals, the next step is to be able to detect which of themovements is associated with the production of residual sEMG signals inrelevant muscles. Then, by allowing the manipulator movement only whenthere is the required mixture of central (e.g., SCP or MAC) andperipheral (sEMG) measurements, the system can teach the person tointegrate cortical activation and muscular performance

In an exemplary embodiment of the invention, a target of therehabilitation process is brain reorganization. Optionally, after aminimal amount of reorganization is detected, this reorganization isused to rehabilitate one or more limbs. Optionally, this “brain”rehabilitation of the limb starts even when there is little or noresidual limb movement in a paretic limb.

In an exemplary embodiment of the invention, one or more cognitiveactivities (but optionally a limited number) are supported by a physicalsystem. Optionally, such support allows a patient to focus his energiesand/or attention on damaged brain areas, reduce fatigue and/or enablethe execution of an otherwise too-complex exercise. In an exemplaryembodiment of the invention, cognitive support is provided by one ormore of visual feedback or anticipatory display (e.g., a 3D movie),audio feedback, kinesthetic feedback from the same or other arm (e.g.,by moving the arm before the exercise or by applying an external forceto aid in recognizing when the arm is off-line), providing a power boostso patient is not required to concentrate on details of carrying outand/or correcting the motion, exemplifying complex motions so lessmemory is needed to recall and/or understand such motions and/orassisting in overcoming pain, for example by allowing patient to feelthe pain ahead of time or by reducing muscle activity of the patient andthus pain.

In an exemplary embodiment of the invention, rehabilitation is enhancedby replacing one or more brain functions by a physical manipulationsystem. In an exemplary embodiment of the invention, kinestheticfeedback analysis is augmented or replaced by a manipulation systemproviding such feedback and/or closing the correctional loop of themotion. Alternatively or additionally, other activities, such asplanning are provided by the system. In an exemplary embodiment of theinvention, kinesthetic feedback is provided as audio or visual feedbackor using tactile feedback (e.g., vibration of vibrator patch on a limb).Optionally, such replacing is reduced as rehabilitation progressesand/or as part of a rehabilitation plan for kinesthetic sense.

A set of uses of some embodiments of the invention, relates to the useof a manipulator to improve measurement capabilities. In an exemplaryembodiment of the invention, repetitive or selectively different motionsby the manipulator are used to better detect brain activation and/ortease apart different sources of brain activity.

In an exemplary embodiment of the invention, repetitive specific motionis used to define a cortical signal, for example, for comparison or fordeciding on treatment. In an exemplary embodiment of the invention, thefact that a repetitive manipulator is used, allows brain signalsrecorded over multiple trials to be combined and averaged. Optionally,the manipulator is used to trigger the movement, so that the signals canbe aligned in time. Optionally, the motion includes motion of a healthyarm and of a paretic arm. The healthy arm movements are optionallydetected by the manipulator and used as the above trigger.

In an exemplary embodiment of the invention, multiple motions arecarried out to determine a motion which is associated with maximalcentral activation (e.g., of areas of the brain associated with theparetic limb). Such determined motions may be used as a starting pointfor rehabilitation, personalized for that patient. Optionally, a rangeof different motions are selected, including motions with minimumactivation and motions with intermediate activations. Optionally, thisallows rehabilitation to selectively attempt easy motions and hardmotions, motions where fast improvement is expected and motions whereslow improvement is expected. Possibly, starting with a maximal signalmotion will provide significant plasticity. Optionally, the lessersignal strength motions are used to assess general progress of thepatient. Optionally, weak signal motions are used to generate a map ofpatient ability and lack thereof.

Optionally, for a particular motion, electrode placement, configurationand/or signal processing may be varied to enhance measurement quality.

In an exemplary embodiment of the invention, a BCI interface is improvedusing repetitive motion. In an exemplary embodiment of the invention, byproviding multiple repetitions, a better optimization of filtrationalgorithms and/or feature extraction algorithms can be provided. In anexemplary embodiment of the invention, this allows a better interface tobe defined for prosthetic devices. In an exemplary embodiment of theinvention, using a controlled manipulator allows a test to be made ofthe effect of small changes in signal detection on movement and viceversa. Optionally, by improving filtration and/or implanting electrodes,detection thresholds can be reduced. Optionally, coherent and patternbased signal processing techniques as known in the art of signalprocessing are used. Optionally, prosthesis tuning is carried out at arehabilitation session, for example, to help train the patient in theuse of the device while at the same time possibly determining moreoptimal BCI parameters.

In an exemplary embodiment of the invention, the number of repetitionsprovided for training a motion (e.g., in one or a small number ofsession over less than a month and optionally less than a week or lessthen a day, or possibly less than an hour) varies between 10 and 1000 ormore, optionally more than 30, optionally more than 100.

Signals Used

Various cortical signals may be used. In an exemplary embodiment of theinvention, event-related potentials are used. Early waves include: PSWPositive slow wave potential (which appears to represent the evaluationof the stimulus: (“I hear a sound; what is it?”)) and NSW Negative SlowWave potential (which appears to represent the orientation reaction i.e.the process of deciding what to do next: (“That sound means to move myleft hand”). Optionally, early waves are not used, but rather laterwaves are used, for example, CNV (which represents the motor responsepreparation that takes place after PSW and NSW) when the response to betaken after S1 is “clear”: (“Let's move my left hand when S2 appears”).It should be noted that each stage is centered at a different part ofthe brain: PSW (Parietal) NSW (Frontal) and CNV (Central). The recordingin FIG. 2 is in C3 and C4 (C3: left central area of the brain; C4 rightcentral area of the brain); there CNV is very prominent. However, anypart and/or multiple parts of event related and non-event relatedsignals may be used. For example, attention related signals may be used,as may alpha and/or other rhythms.

In one example, BP is used. BP represents a physiological responsesimilar in nature to CNV (brain activation as preparation to execute amotor response). However, in the case of BP, there is no neuralprocessing/examination related to processing the nature and meaning ofthe stimulation. Therefore, BP typically involves mainly the activationof motor and areas in the cortex while CNV involves the activation ofother sites in the brain as frontal and central cortex.

In an exemplary embodiment of the invention, CNV is particularly usedwhen device 600 provides sound stimulation to indicate to the patientvarious stages of the movement loop to alert him/her that another stepin a rehabilitation exercise is about to begin. This may assist inentraining the patient to perform movement in sync with pre-plannedexercise. This is similar to the S1 S2 type of paradigm involving CNV.

As described above, the signals are optionally composite (scalar)signals. However, a grid array or other multi-value structure, such as avector, may be used as the signal which is measured and/or trained.Optionally, exact grid positions and associated values are aimed forand/or acquired. Alternatively or additionally, a relative pattern, forexample, greater activation on one motor area, is a target of therehabilitation. Optionally, selecting grid area targets may be used tohelp shift brain activity. For example, causing a patient to prefer tohave pre-motor activity 1 cm away from its “natural” location, may beused to shift the pre-motor area and allows for use of the freed areafor another purpose. In another example, control of an activation areais used to intentionally suppress taking over of brain areas byfunctions which it is not desired for them to take over, for example, afunction which the patient is not exercising and might otherwiseregress. Optionally, moving an activation area is used to intentionally“erase” existing activity, for example, activity associated with aphantom limb.

In an exemplary embodiment of the invention, desired activation areasare decided by a treating physical, for example, based on areas whichare known to be damaged or undamaged and/or based on a plan forreorganization of the patient's brain. Optionally, the plan is changedas the ability of the patient to exhibit motion and/or other types ofplasticity is assessed.

Optionally, incorrect and/or undesirable activation is “rewarded” by abad-sounding sound and/or by preventing motion. Optionally, a continuousfeedback is provided, in degree of resistance to motion and/orassistance to motion being dependent on degree of undesirability ordesirability of an activation. Optionally, different stages in anactivation (e.g., BP, PMP) are entrained separately.

Detailed Examples of Use of System 600

The following sections describe exemplary uses of system 600 forrehabilitation in association with cognitive measurements, in accordancewith exemplary embodiments of the invention. More detailed and explicitexamples are described first. It should be appreciated that these areonly examples and not all the details described need to be provided inevery embodiment of the invention.

Exemplary Recording Setup

FIG. 6B shows a proposed recording arrangement to monitor MAC and theexpected signals related to a left arm movement (deeper BP and higher MPrecorded over the right hemisphere). It should be noted that (unlikeprevious Figures) negative deflection is upwards.

Example of Calculation of Bilateral Cortical Activation

This exemplary exercise features the synchronized bilateral movement ofarms, (paretic and healthy), in a mirror like fashion; so that the sameset of bilateral homologous muscles are activated in the sameprogressive fashion along the movement path. In some cases, theserequirements may be relaxed somewhat. Generally, however, a matching ofthe muscles which actually do the motion is desired, for example, sothat the motion plans and/or feedback analysis are easier for thepatient to transfer.

During each cycle (movement loop) and for each one of the peripheralmuscles monitored by the sEMG facility, (e.g., a four muscle sEMGarrangement) system 600 performs/displays the followingmethodological/processing stages (also shown as a flowchart 700 in FIG.7), with the caveat that (a) the particular numbers shown are onlyintended to be examples and (b) some of the acts described below may beomitted and/or changed in order and/or replaced by other acts:

-   1. Upon each start of each movement loop, display a special    audio-visual stimulus that acts as t0 synchronization cue of the    movement loop. At t0 all data is refreshed and an internal clock    starts to count (702).-   2. Record continuously a self-refreshing time series of optionally    pre-filtered and/or smoothed (e.g., using a suitable moving average    method) slow cortical data (optionally recorded from electrodes C3    and C4) over X1=500 msec (the X1 variable is optionally changed    according to experimental adjustment). This data has a length that    can cover the late part of BP (BP2) and the beginning of the    muscular activation (MP) (FIG. 1.). The sequence of data in each MAC    signal between BP2 and MP typically shows a sudden shift from    maximal negativity at the end of BP2 to a maximal positive value    after the muscle starts to contract. In an exemplary embodiment of    the invention, this change is used for detection and quantification    purposes, as it is typically easily discernable in MAC signals. This    may be alternative or additional to a conventional experimental    approach to MAC in which the interest is in the actual shape of the    MAC, particularly with respect to the degree of negativity of the BP    and CNV. In order to improve signal to noise ratio a summation and    averaging process over repeated similar signals/trials is used so    that noise cancels out and a cleaner averaged signal emerges from    the process. In this embodiment (detecting the transition), reliable    data is optionally extracted form a single (or small number) trial    and the BP2-MP transition shift possibly provides the means to    execute quantification/biofeedback steps for every single muscle    contraction of a single trial (704).-   3. Identify the onset of the sEMG on the healthy side as trigger    (TM) (706).-   4. Store time of TM (t1) in the internal clock (708).-   5. Calculate the delay to contraction (D=t1−t0) and compare with an    expected value (optionally provided from previous loops and/or a    “personal signature”, described below). Each one of the    agonist/antagonist muscles involved sequentially in a fixed (in time    and space) movement will typically have its own characteristic time    of contraction. The series of Ds over each movement loop optionally    serves as a measure of the synchronization control of the movement    as a whole. (710)-   6. Upon monitoring TM, (for each muscle), calculate the differential    values from the data present in the self-refreshing time series data    array recorded continuously (see act 2). Store discrete differential    values for a period from 250 msec before TM until 250 msec after TM    (DIFF TM). Here the marked deflection between the largely negative    late BP2 stage and the largely positive early MP stage gives a    series of differential values with a positive spike-like peak shape    over this phase of the MAC. (720)-   7. Establish maximum value of DIFF TM (DIFF TM Max). This event    should generally take place immediately after the start of muscular    contraction t1. (716)-   8. Calculate and store time of DIFF TM Max (t2) (718)-   9. Calculate t2−t1=SYNC. Values of SYNC <0 and >50 msec are possibly    erroneous and may indicate bad synchronization between cortex    activation and motor performance or may be an artifact. SYNC is    optionally used as a self-testing parameter. (712)-   10. Integrate (mean) values for 400 msec; 200 msec before and 200    msec after DIFF TM

Max (Imax) and store this bit of data for each muscle bilaterally. Thewindow of differential data to be integrated is optionally “trimmed”from 500 msec in previous stages to 400 msec in order to avoid theinfluence of semi-raw data above (before), the maximal negativity pointduring BP2 or data below (after), the maximal positivity point duringMP. (714)

-   11. Calculate Imax Paretic/Imax Healthy*100=% HCA (% of Homologous    Cortical Activation) for each part of Homologous muscles in the    upper arm. % HCA optionally provides an immediate value for the    degree of activation opposite to the paretic side in relation to the    healthy control. (722)-   12. % HCA is translated into a suitable 1-100 (an arbitrary scale)    variable pitch sound delivered at the end of each contraction of    each muscle as audio feedback to patient. Since it can be important    to provide accurate on-line biofeedback there is optionally provided    a “safety valve” that will prevent the display of erroneous    biofeedback: Audio biofeedback results are displayed, and % HCA are    stored for subsequent post-processing only if SYNC <0 and >50 and D    is as expected from personal signature. The series of audio    displays, (one after each muscle contraction), described in this    section represent a form of continuous audio biofeedback along the    movement loop. This feature may enable the user to identify    particularly difficult stretches along the path. When a continuous    series of high pitch sounds are heard all through the loop the user    can understand that that particular movement is now learned. Other    audio feedback may be used instead. Optionally, visual or tactile    feedback is used, for example, to complement audio feedback for or    patients with hearing problems. (724) 13. Upon the completion of    each device operation cycle, calculate mean values of % HCA for all    muscles during the loop (CYCLE % HCA). Store CYCLE % HCA for each    loop and sound (730) a rather longer 1-100 variable pitch sound    which represent the sound feedback for the whole cycle. In this way    the user can be provided with online continuous feedback, feedback    at the end of each cycle and/or an assessment feedback value at the    end of a series of cycles at the end of a rehabilitation session.    HCA is optionally used as an assessment measure. (728)

In an exemplary embodiment of the invention, short windows (e.g., 200msec) are used so as to better compare pairs of muscles. As the windowis made longer, the difference may become less distinguishable. Theactual delays may change, for example, based on the patient and/orprevious records thereof.

In an exemplary embodiment of the invention, various thresholds aredefined as quality indicators if thresholds are not met (e.g., for ameasurement), then the recording is optionally dropped as potentiallysuffering from a quality problem.

Example of Calculation of Mono-Lateral Cortical Activation

This exemplary exercise involves the work with a single paretic arm. Inthis embodiment the methodology/processing is similar to the onedescribe previously (for bilateral activation) but the results areoptionally compared with those of a trial completed previously with thehealthy contra lateral arm.

If the patient is unable to carry out the exercise loop with thestrength of his own muscles, system 600 may become active and move thearm (totally or just partially, adding its force to the one generated bythe subject). The triggering schedule in this case is optionallyprovided by system 600 using pre-programmed time cues calculated fromthe patient signature with the healthy arm in previous trials. Forexample, the timing of various muscle movements for a healthy arm may bestored and then used for the paretic art, optionally slowed down tomatch a generally slowed down condition of the arm. The slowing down isoptionally determined by measuring a short sequence of motion of theparetic arm and comparing this sequence to the stored values for thehealthy arm.

An example of an exercise follows, again, with the numbers and/or theacts being exemplary only:

-   1. Before the start of each movement loop, display a special    audio-visual stimulus (S1) that acts as t0 synchronization cue of    the movement loop. At t0 all data is refreshed and a device internal    clock starts to count. For this type of exercise the user is    instructed that after t0 s/he will be asked to contract a muscle and    start a movement by displaying a second time cue t1 (described in    act 3.)-   2. Record continuously a self-refreshing time series of optionally    pre-filtered and/or smoothed (e.g., using a suitable moving average)    slow cortical data (recorded from electrode over the contra lateral    central zone; C3 or C4) over X1=500 msec (X1 value can be changed,    for example, according to experimental adjustment).-   3. Relate to a time (t1) for the contraction of a particular muscle.    (This time has been previously calculated for the healthy arm). At    this stage system 600 provides another time cue (S2) signaling the    start of the contraction.-   4. Calculate the differential values from the data present in the    self-refreshing time series data array recorded continuously (see    act 2.). Store discrete differential values for a period from 250    msec before S2 until 250 msec after S2 (DIFF S2).-   5. Establish maximum value of DIFF S2 (DIFF S2 Max). This event    should generally take place immediately after the start of muscular    contraction t1.-   6. Integrate (mean) values for 400 msec; (200 msec before and 200    msec after) DIFF S2 Max (Imax) and store this bit of data for each    muscle.-   7. Calculate Imax Paretic/Imax Healthy (previously recorded)*100=%    HCA (% of Homologous Cortical Activation) for each part of    Homologous muscles in the upper arm.-   8. % HCA is translated into suitable 1-100 variable pitch sound    delivered at the end of each contraction of each muscle as audio    feedback to patient.-   9. Upon the completion of each device operation cycle, calculate    mean values of % HCA for all muscles during the loop (CYCLE % HCA).    Exemplary Activation of Damaged Side of Cortex from Healthy Contra    Lateral BP

In an exemplary embodiment of the invention, another mode of operationof system 600 is the detection and use of a BP2-MP time cue from thehealthy side, (as described above), in order to stimulate the contralateral (damaged side) of the cortex. Stimulation can be, for example,with an electromagnetic coil similar to the ones used in conventional EMCortex Stimulation. Alternatively or additionally, stimulation isprovided by using system 600 to move the paretic limb.

This embodiment exemplifies a kind of FES (Functional ElectroStimulation) that is based on the activation of the contra-lateralhealthy side while performing a bimanual mirror like type of movement asmentioned above.

In an exemplary embodiment of the invention, what is desired is not toprovoke a contraction but just to stimulate below the threshold ofcontraction so as to assist any endogenous production of MP to achieveover-threshold values and be effective in order to produce movement.This particular arrangement may help the user also to associate centralactivation with peripheral movement, possibly encouraging plasticity.Optionally, actual motion is also helped by manipulator 604, possiblyfurther reducing the threshold of activation in the brain and/ormuscles.

Alternatively or additionally to electromagnetic or electricalstimulation (e.g., using a DC current), in an exemplary embodiment ofthe invention, mental imagery or other cognitive activity caused bysystem 600 has an effect of activation, optionally a visual displayand/or a physical motion. Optionally, the assistance of system 600 actsto lower the threshold, rather than to activate muscles. Optionally, theassistance of system 600 acts to reduce mental concentration requiredfor planning the details of the motion and/or performing real-timefeedback to ensure the motion is correct and, instead, a patient isfreer to concentrate on planning of the motion. In an opposite usage,the fact that system 600 moves a limb allows a patient to clearlymentally image the motion, so the planning stage is made easier, leavingmore attention to other stages.

In one example, assistance is by the system providing a power boost tomotions generated by the patient. In another example, assistance is bythe system applying a force that returns the limb to the correct path(e.g., instead of or in addition to such force applied by the patient).In another example, assistance is by the system moving the limb throughthe required motion, to help create suitable mental imagery or learn theexpected kinesthetic feedback. Similarly, a patient, by such assistedmotion, can learn when to expect pain, or which parts of the motionmight require more concentration and/or planning. In another example,the system provides one dimensional property of the motion, such as thetempo of the motion (e.g., velocity amplitude) with the patientproviding another dimensional property of the motion, such as direction,or vice-versa. In another example, the system repeats a motion carriedout by the patient with the same or opposite limb, allowing the patientto “merely” repeat a previous planning or execution activity.

The system optionally provides a score during such a pre-test, showingthe patient where more effort will be required during voluntary motion.Alternatively or additionally, as noted above, such feedback can beprovided during motion, for example to assist in attention.

Example of Using SCP as Part of a Rehabilitation Process

Slow Cortical Potentials (SCP) represent another type ofelectrophysiological signal recorded from the scalp that can betranslated into parameters able to interact with the mechanical and/orprocessing modules of system 600, especially for use in rehabilitation.

The use of SCP recordings integrated into system 600 (or otherrehabilitation system) can be particularly useful in the very earlystages of rehabilitation, when no sign of movement or muscular activityare present. In this case the SCP signals can be used to move the robotand hence to allow movement of the paretic hand accordingly. Thus, apatient can receive feedback on intentions, possibly assisting in theplasticity process. It should be noted that feedback can be providedvisually and/or by moving a robot affecter. However, actually moving apatient's limb may assist in the rehabilitation or motor control.

By using system 600 with SCP, the patient can learn to control the SCPby observing the effects of brain activation or inhibition on theposition of a limb. Optionally, a pre-selected flexion/extension path isused for such training. Alternatively, more complex motions, such ascircular motion may be used. In some embodiments of the invention, brainsignals are used to initiate and/or stop motions. In others, they areused to modify existing motions. Alternatively or additionally, they areused to allow a motion to continue, as long as the brain activitymatches a desired pattern.

In an exemplary embodiment of the invention, signals from the brain areacquired by electrodes on the scalp, (SCP), and processed to extract aparameter directly proportional to the sign and/or amplitude of thesignal. This parameter is then used to direct the manipulator 604 tochange position of the arm according to the various levels of brainactivation and/or inhibition in a pre-selected flexion/extension path.In an exemplary embodiment of the invention, at the beginning ofrehabilitation the movement follows a very simple mono-directional pathand reflects the activity recorded from a single electrode over thescalp. FIG. 8 shows actual SCP signals recorded from a subject producingcortical activation, and cortical inhibition, which signals may be usedto drive mechanical motion in accordance with some embodiments of theinvention.

Optionally, the larger the degree of activation the more complete thedegree of flexion from a middle point, the larger the degree ofextension from a middle point of the motion.

Optionally, in later stages, the patient can use a multiple electrodearrangement covering several sites over the scalp. The combined activityfrom all these electrodes can be then analyzed and processed so tofacilitate the entrainment of more complex movement paths.

Mu Rhythm Exemplary Implementation

Alternatively or additionally to SCP signals, Mu rhythm recordingsprovided by system 600 (or another rehabilitation system) may beparticularly useful in the very early stages of rehabilitation, when nosign of movement or muscular activity are present. In an exemplaryembodiment of the invention, some movement of the robot will betriggered by the learning and manipulation of one or more of Mu, SMRand/or Beta rhythms.

In an exemplary embodiment of the invention, signals from the brain areacquired optionally by electrodes over C3 and C4 on the scalp, andprocessed to extract a parameter directly proportional to the degree ofdesynchronization of the recorded rhythm. This parameter is then used todirect the mechanical modules of the rehabilitation device to changeposition of the arm accordingly.

Optionally, the Mu rhythms implementation is used in the early stages ofrehabilitation primarily to move the robot in a purely mono-directionalfashion and without much involvement of peripheral structures (nervesand muscles). Optionally, different movements are used to traindifferent types of control over the brain and/or different control fordifferent movement conditions (e.g., different limbs and/or differenttrajectories). As also described herein, manipulator 604 and/or FES 622may be used to provide motion enhancement (or motion) synchronized tothe cortical activity.

Examples of Linking of Central Activation and Movement Use of MACPotentials Related to Voluntary Movement

Briefly, MAC potentials include the early Readiness or “Bereitschaft”Potentials related to the planning of a movement which involves twonegative waves preceding the movement: the early one which appears tothe related to the activation of mesial frontal cortex and the“supplemental motor area” which is symmetric and bilateral in nature, alater negative wave just before the execution of the movement related tothe activity of cortical-spinal tract concerning efferent discharges ofpyramidal tract which is maximal contra-lateral to the movement. Thebeginning of the movement is marked by a strong positive wave thatstarts with the onset of muscle contraction and includes furtherpositive waves reflecting first central and later peripheral feedbackfrom muscle and joints. These positive waves are maximal when recordingat the top of the scalp at Cz.

In an exemplary embodiment of the invention, the recording of bilateralMAC is used to monitor assess and/or entrain with system 600. Thisapproach optionally compares the performance of both arms (one normaland the other paretic) and the link with the movement (muscularcontraction) is intrinsic to this approach.

Use of SCP Signals in BCI Device Entrainment

In an exemplary embodiment of the invention, SCP signals are trained tocontrol a BCI device. Such signals may be based on generalizedthalamo-cortical and intra-cortical activation/inhibition. The more thethalamo-cortical and intra-cortical activation the bigger the“negativity” of the SCP signal; the less the thalamo-cortical andintra-cortical activation the bigger the “positivity” of the SCP signal.

In an exemplary embodiment of the invention, SCP training & control isused to add a neurological dimension to the therapeutic use of system600.

In an exemplary embodiment of the invention, manipulator 604 is movedaccording to the characteristics of the SCP signal and/or according tothe integration of features of various SCP signals recorded from variouselectrodes placed at different sites of the scalp. This approach canfacilitate the creation of movement even when there is total paresis.This may have significant psychological and physiological positiveimplication for the patient.

Optionally, an ultimate purpose of system 600 is to encourage brainhealing and plasticity in order for the patient to, first, initiatemovement of a paretic member and eventually to regain full movement.Optionally, this is achieved, at least in part, by linking the activeneuronal loops in the brain cortex related to activation/inhibition asreflected in the SCP with the motor knowledge/rehearsal/activation thattakes place while planning and executing the movement.

Optionally, a temporal and/or intentional linkage is created between twoor more of the following three factors:

(a) the cortical activity being manipulated (by the patient) to controlthe BCI device;

(b) the passive or active movement, generated or monitored by system 600and its various triggering facilities; and

(c) the exact sequence of neurological events taking place at centraland peripheral cells of the motor path involved in that particularmovement.

In an exemplary embodiment of the invention, the sequence ofneurological events is detected using EEG and/or fMRI and linked to theother rehabilitation activities, for example, by providing positivefeedback using system 600. Optionally, the positive feedback is bymotion. Alternatively or additionally, the positive feedback is byvisually presenting whether a correct neural pathway is being activated.Optionally, the neural pathway that should be generated is estimated byviewing pathways for motions that do not involve paretic limbs or thosefor which some motion is carried out in a paretic limb.

Optionally, once the BCI is entrained, it may be used for controlling aprosthesis, not during a rehabilitation session.

In an exemplary embodiment of the invention, the ability to repeat amotion exactly many times is used to acquire more complete statistics ofbrain activation. Optionally, the use of repetitions allows a betterfiltering and/or averaging of noise. Optionally, this allows a moreprecise pattern recognition and/or signal processing for detectingparticular SCP (or other) signals for the BCI system.

Other linking methods are described herein and may also be used forcontrolling prostheses.

Use of Residual sEMG to Modulate SCP Based Device Movement

In an exemplary embodiment of the invention, residual (e.g., withoutcontraction) sEMG is used to modulate SCP based movement.

Optionally, after the patient learns to move manipulator 604 withhis/her SCP signals, any residual sEMG peripheral signal detected overrelevant muscles is used as a co-trigger, (e.g., with the relatedcentral signal SCP or MAC), to move the manipulator 604 and in this waythe patient possibly integrates cortical activation and muscularperformance.

Use of Agonist/Antagonist sEMG Discrimination to Modulate SCP BasedMovement

Another optional method of linking cortical activation and muscularperformance takes into consideration the particular features of themovement the patient is trying to learn to execute.

In this approach the degree of contraction and relaxation of the musclesinvolved in a particular movement, (e.g., as reflected in the amplitudeof the RMS sEMG signal recorded over each muscle), is used asbiofeedback information that is provided to the patient (e.g., bydisplay) to activate or inhibit SCP (by the patient).

Contraction is defined as an increase of sEMG above an average RMSbaseline level established beforehand, and relaxation a decrease of sEMGbelow the average RMS baseline.

Example of Early Rehabilitation Stage Implementation (Total Immobilityor No sEMG)

In this exemplary methodology, in early stages of the rehabilitationprocess, when no movement or residual sEMG is available to be recordedfrom the paretic member, the sEMG recordings are done on the healthy armas the movement is performed by the healthy arm attached to one side ofa two sided system 600 (e.g., with two manipulators 604) and accordingto the force created in the healthy arm. The other manipulator of therobot is attached to the paretic arm and is programmed to move (ormodify its movement) to be in a similar path as the contra-lateralhealthy limb ONLY when correct activation or inhibition is recorded overthe relevant SCP signal.

Following are exemplary acts in such training Not all the acts areessential and some may be omitted, changed in order, have parameterschanges and/or be replaced by other acts:

-   1: Determination of therapeutic movement: First the physiotherapist    determines the movement loop to be learned according to his/her    professional assessment of the patient's restrictions. Optionally,    system 600 is used to assess the patient's restrictions.-   2: Definition of the movement in sEMG terms: The agonist and    antagonist muscles involved in that particular movement are defined    and their respective contraction and relaxation periods in the    movement loop are recorded and established. This may be performed,    for example, automatically by system 600 once the motion is    selected.-   3: Relate single (agonist) muscle contraction to SCP activation:    Take major agonist muscle involved in the movement loop and each    time it is about to contract (e.g., 0.5 sec before) ask the patient    to generate a synchronous SCP activation (more negativity) on an    electrode placed over the contra-lateral side of the motor cortex.    This may take some practice.-   4: Reward synchronous cortical activation: If SCP activation was    achieved, reward by moving paretic arm together with healthy one.    Other rewards may be used as well or instead.-   5: Relate single muscle relaxation to SCP inhibition: Take same    major agonist muscle involved in the movement loop and each time it    is about to relax (e.g., 0.5 sec before) ask the patient to generate    a synchronous SCP inhibition (more positivity) on an electrode    placed over the contra-lateral side of the motor cortex.-   6: Reward synchronous cortical inhibition: If SCP inhibition was    achieved, reward by moving paretic arm together with healthy and    completing the loop. Optionally, rewarding is not carried out for    every correct motion.-   7: Relate main antagonist muscle relaxation to SCP activation; and    antagonist muscle contraction to SCP inhibition: acts 3 and 5 are    repeated, with the antagonist muscle. It should be noted that while    agonist contraction is trained with SCP activation, antagonist    contraction is trained with SCP inhibition; likewise, when agonist    relaxation is trained with SCP inhibition antagonist relaxation is    trained with SCP activation.-   8: Reward accurate synchronous cortical activation and inhibition    while relaxing and contracting the antagonist muscle: This is    similar to acts 4 and 6 but with the antagonist muscle. If SCP    activation was achieved before antagonist relaxation and if SCP    inhibition was achieved before antagonist contraction, reward by    moving paretic arm together with healthy arm. It should be noted    that different rewards and/or feedbacks may be used to signal, for    example, correctness of amplitude, timing and/or type of activation.-   9: Relate a pair of agonist/antagonist muscle contraction/relaxation    to SCP activation: SCP activation (more negativity) is trained to be    related to agonist contraction and antagonist relaxation in the    first phase of the movement.-   10: Relate a pair of agonist/antagonist muscle    relaxation/contraction to SCP inhibition: SCP inhibition (more    positivity) is trained to be related to agonist inhibition and    antagonist contraction in the second phase of the movement.-   11: Reward accurate synchronous cortical activation and inhibition    while working with a pair of agonist/antagonist muscles.-   12: Repeat acts 9 to 11 but with two agonist/antagonist pairs of    muscles: This involves the recording of sEMG from 4 (or more)    different muscles, optionally always relating agonist/antagonist    muscles contraction/relaxation to SCP activation and    agonist/antagonist muscles relaxation/contraction to SCP inhibition.    Then reward accurate performance as before. This last act is shown    in FIG. 10.

Optionally, after the activities of muscle pairs are linked, additionalrehabilitation designed to target single ones of the muscles isperformed.

FIG. 11 is a flowchart 1100 of an exemplary method of jumpstarting arehabilitation process, in accordance with an exemplary embodiment ofthe invention. In an exemplary embodiment of the invention, the methodof FIG. 11 is configured so that any motion or intent detected by thesystem will generate a noticeable feedback to the patient. Optionally,detection is skewed towards detecting motion, even if what is detectedis noise. Failure to detect a motion signal is optionally dealt with bychanging the detection method and/or a stimulation method.

At 1102, a stimulation is optionally provided to the patient, to causethe patient to move or want to move. Various stimulation methods may beused, for example, audio prompts, audio instructions, displays,stimulation of nerves, CNS stimulation and/or mechanical vibrations.Optionally, stimulation is in response to a readiness signal detected inthe patient.

In an exemplary embodiment of the invention, the stimulation provided isguided mental imagery. Optionally, the patient's eyes are closed duringthe imagining. Optionally, visual assistance is provided to the patient,for example, one or more of a graphic sequence, a processed image orvideo sequence and a static display. Optionally, the processed image orsequence comprises an image of the patient processed to show motion, forexample, by mirror, or by segmenting the patient's limbs and movingthem, in the image. Optionally, once the movement is completed, acomparison is made to see if the motion matched the imagery. Optionally,the stimulation is changed periodically, to prevent habitation by thepatient. Optionally, however, for jumpstarting movement, such comparisonis less important than actually achieving motion at all or which isanywhere near the intention.

Alternatively or additionally, the stimulation comprises moving the limbusing device 600.

At 1104, the patient is expected to try to move and/or try to initiate amotion or other action plan.

At 1106, various physiological measurements are made to see if there areany hints of motion, for example, measuring sEMG and/or actual motion.

At 1108, neurological measurements are made alternatively oradditionally to physiological measurements. Optionally, a vector ofneurological measurements is defined, for example including varioussignal parameters optionally associated with areas of measurement.

At 1110, the measurements are analyzed to see if there are anyindications of motion or intent of motion. If so, a motion or otherfeedback is carried out at 1112. Optionally, any existing motion isamplified.

At 1114, stimulation parameters are optionally changed, for example, toprevent habitation or as part of a search among different stimulationmethods and/or parameter values for a stimulation which will work.Various search methods are known in the art. A particular optionalchange in stimulation is an increase in amplitude of stimulation.

At 1116, the measurement method and/or signal processing method ischanged. For example, an area to which electrodes are connected may bechanged.

It is expected that at least for some patients, the method of FIG. 11,if repeated often enough, will elicit some movements or at leastindications of the generation of an intention to move, which indicationscan be a starting point for further rehabilitation.

Example of Later Rehabilitation Stage Implementation (Some Mobility orResidual sEMG)

At a later stage of the rehabilitation process, when some residual oreven effective sEMG is available, the sEMG recordings are optionallycarried out on the paretic arm and the SCP measurements are, as usualrecorded centrally or over the contra-lateral side over the motor cortexCz and C3 or C4).

In an exemplary embodiment of the invention, the movement is performed,by the paretic arm attached to a single manipulator system 600.

Optionally, the same schedule is followed as before (acts 1 to 12 justdescribed). Optionally, the reward is given in one or more of thefollowing forms:

-   -   System 600 can assist the patient in performing the movement by        starting the motion and letting the user to continue performing        it.    -   System 600 can assist the movement by reducing the overall        resistance to the movement loop.    -   System 600 can assist the movement by providing suitable        supra-threshold FES to enhance contraction of the various        muscles at the expected time and/or part of the movement loop.    -   System 600 can provide audiovisual reward.

Integrated Example

Arm flexion and extension generally requires the synchronized action ofthe Biceps and the Triceps muscles. For example: Biceps contract/Tricepsrelax lead to flexion; Biceps relax/Triceps contracts leads toextension.

Optionally, a patient suffering of total arm hemi paresis with the rightside affected, is treated using the following rehabilitation acts:

-   1. Teach and train patient to generate SCP activation over C3    (contra-lateral to the paretic arm) or Cz (central point) 0.5-1 sec    before the start of a contraction of the left Biceps (e.g.,    identified by increase of sEMG RMS). The patient is attached to a    bi-manipulator system 600 and trying to produce a bilateral arm    flexion.-   2. Reward synchronous cortical activation by flexing the paretic arm    together with the healthy left arm.-   3. Teach and train patient to generate SCP inhibition over C3    (contra-lateral to the paretic arm) or Cz (central point) 0.5-1 sec    before the start of a relaxation of the left Biceps (e.g., detected    by decrease of sEMG RMS). The patient is attached to a    bi-manipulator system 600 and trying to produce a bilateral arm    extension.-   4. Reward synchronous cortical inhibition by extending the paretic    arm together with the healthy left arm.-   5. Teach and train patient to generate SCP activation over C3    (contra-lateral to the paretic arm) or Cz (central point) 0.5-1 sec    before the start of a relaxation of the left Triceps (e.g., detected    by decrease of sEMG RMS). The patient is attached to a    bi-manipulator system 600 and trying to produce a bilateral arm    flexion.-   6. Reward synchronous cortical activation by flexing the paretic arm    together with the healthy left arm.-   7. Teach and train patient to generate SCP inhibition over C3    (contra-lateral to the paretic arm or Cz (central point) 0.5-1 sec    before the start of a contraction of the left Triceps (e.g.,    detected by increase of sEMG RMS). The patient is attached to a    bi-manipulator system 600 and trying to produce a bilateral arm    extension.-   8. Reward synchronous cortical inhibition by extending the paretic    arm together with the healthy left arm.-   9. Teach and train patient to generate SCP activation over C3    (contra-lateral to the paretic arm) or Cz (central point) 0.5-1 sec    before the start of a contraction of the left Biceps accompanied by    the associated relaxation of the left Triceps (e.g., detected by    increase of sEMG RMS over the Biceps and decrease of sEMG RMS over    the Triceps). The patient is attached to a bi-manipulator system 600    and trying to produce a bilateral arm flexion.-   10. Reward synchronous cortical activation by flexing the paretic    arm together with the healthy left arm.-   11. Teach and train patient to generate SCP inhibition over C3    (contra-lateral to the paretic arm) or Cz (central point) 0.5-1 sec    before the start of a relaxation of the left Biceps accompanied by    the associated contraction of the left Triceps (e.g., detected by    decrease of sEMG RMS over the Biceps and increase of sEMG RMS over    the Triceps). The patient is attached to a bi-manipulator system 600    and trying to produce a bilateral arm extension.-   12. Reward synchronous cortical inhibition by extending the paretic    arm together with the healthy left arm.-   13. Once the above training is successfully accomplished, more    complex movement, such as involving two pairs of agonist/antagonists    may be entrained. For instance training to regain the flexion of the    shoulder (bending the joint resulting in a decrease of angle; moving    the upper arm upward to the front) and extension of the shoulder    (straightening the joint resulting in an increase of angle; moving    the upper arm down to the rear). The flexion and extension of the    shoulder require the activity of more than one pair of    agonist/antagonist muscles. Optionally, the training is continued    recording sEMG over, for example, the Biceps/Triceps and the Deltoid    Anterior/Deltoid posterior arrangement.

In an exemplary embodiment of the invention, a “personal signature” ofparameters for movement, associated MAC (and/or other brain signals)and/or coexisting sEMG are established for a healthy arm and even insome cases bilaterally for totally healthy individuals. These areoptionally used as standards against which performance of paretic armsduring the rehabilitation process are compared and/or assessed,qualitatively and/or quantitatively. In an exemplary embodiment of theinvention, a patient is rehabilitated to have motion which matches thepatient's signature or match that of an “expert” (e.g., a Tai-Chi expertor a dancer).

Brain-Computer Interface (BCI) Embodiment

As a replacement for the brain's normal neuromuscular output channels, aBCI depends on feedback and on adaptation of brain activity based onthat feedback. Thus, a BCI system must provide feedback and mustinteract in a productive fashion with the adaptations the brain makes inresponse to that feedback. In a BCI apparatus according to someembodiments of the invention, the feedback will be given by means ofrobotic movements and visual/acoustic feedback on the computer screen.

SCP-Robot for Enhancing Cortical Reorganization in Stroke Patients

One application of the SCP method is to use it for a directtreatment-induced cortical reorganization in stroke patients. Byexecuting robotic movements via SCP control, an SCP-based BCI method maybe used to enhance cortical reorganization directly, independently frommotor capability.

In an exemplary embodiment of the invention, patients will be trained tomodify the lateral difference in precentral slow potentials usingneurofeedback and instrumental learning procedures (optionally receivingreinforcements, such as the success in moving the robotic arm with theaffected limb). Feedback of the difference between left- andright-precentral brain activity will be provided and patients willoptionally be reinforced if they will produce the required changes inbrain activity upon discriminative stimuli; for example, highernegativity in amplitude over the damaged areas than negativity generatedover the contralateral undamaged areas.

In an exemplary embodiment of the invention, changes in activity of thebrain is used as a measure of plasticity, e.g., it is assumed thatpatients who achieve higher cortical activity over the injured areaswill exhibit more efficient (e.g. fast, accurate, preferential)responding with the hand contralateral to the hemisphere (the affectedhand which is attached to the robot), in which brain activity wasincreased.

Brain activity recording is optionally carried out with singleelectrodes or a dense electrodes array which will be attached to thescalp via an EEG-cap. In a case of lesion in the left hemisphere(affected right hand), for example, the patient will be asked toincrease brain activity over this hemisphere, and/or over thespecifically lesion sites (e.g., if known, for example using CT, MRI,PET, TMS, HEG, fMRI, transcarnial ultrasound for blood flow measurement,Magnetoencephalography MEG or any other brain imaging techniques) incomparison to the intact right hemisphere and/or specifically undamagedsites, so that a balance of excitability between the two hemispherestoward a normal condition can be aimed for, established and/ormaintained. Optionally, in addition to measuring motor outcomes (e.g.,questionnaires and measurements by system 600), brain imaging techniquesthat enable to determine exact damaged sites (before treatment), as wellas alternations in cortical reorganization during and after treatment,for example, a fMRI scan every week over several weeks of treatment, areused, for example to determine treatment-dependent alterations incortical reorganization over time.

In an exemplary embodiment of the invention, brain imaging techniquesare used to detect the edge of a damaged area so that exercises and/oractivation can selectively focus on reactivating this edge. The edge ofthe damaged area is possibly identified by its excitation being erratic.

In an exemplary embodiment of the invention, brain reorganization isassessed without using imaging techniques or is used to support suchmeasurements. In an exemplary embodiment of the invention, corticalreorganization is assessed from alteration in brain activity. Forexample, if a patient is able to increase the level of activity (e.g.higher amplitudes) over the damaged cortical area during treatment withsystem 600, and if this activation correlates with movement improvementof the affected hand, it is optionally assumed that some underlyingcortical networks became more active than before, which implies brainreorganization and/or other improvement. In another example, if apatient increases brain activity over the undamaged hemisphere, and thisactivation correlates with better motor functioning of the affectedhand, it is optionally assumed that the motor cortical regions of theundamaged hemisphere control the hand movements, which implies brainreorganization.

In an exemplary embodiment of the invention, brain imaging techniquesare applied at various stages of the rehabilitation, for example, at astart thereof, when stages are complete or goals reached and/orperiodically. Optionally, rehabilitation is carried out using brainimages, such as fMRI. Optionally, the imaging is not used for allrepetitions, but only for some, for example, to note that an exercise(intra-cranial) is being carried out.

In an exemplary embodiment of the invention, high cost imagingtechniques (including high resolution EEG) are made more cost effectiveby using such techniques to interpret low cost techniques, such as EEG.In an exemplary embodiment of the invention, a calibration session iscarried out in which the patient is caused to produce a certain desired(for tracking) brain activity and this activity is both imaged using ahigh cost technique and by a low cost technique. In this regard costmeans any cost, such as techniques which come at a cost to the patient(such as radiation imaging) or at a cost to the rehabilitation process(such as requiring the patient to remain motionless). One the targetactivity can be recognized based on the low cost method, this low costmethod may be used for feedback during rehabilitation. Optionally, thecalibration is carried out long enough and/or repeated to ensure thatthe low-cost method has an actual correlation with the high cost method.Optionally, the calibration session is used to assess the degree ofcorrelation, which may assist, for example, in deciding duringrehabilitation, which measure to trust and/or what weighting functionsto use.

Mu-Rhythm-Robot for Enhancing Cortical Reorganization in Stroke Patients

In an exemplary embodiment of the invention, in a series of exercisesthe patient is asked to execute robotic movements in various directionsand plans and EEG electrodes or an EEG-cap are used to measure themu-rhythm activity over the motor areas in accordance with the executionof these movements. At the second stage of these exercises the patientis asked to imagine the executed movements, trying to cause themanipulator 604 to move in the desired direction(s). The combination ofthe sensory (imagination) and motor (robot movements) channels possiblywill enable to teach the patients to control exactly the neuronalnetworks involved in movement executions, possibly achieving a directcontext-dependent neural activity.

Cortical “Fingerprints” of Specific Movements/Movement's Intention

In an exemplary embodiment of the invention, a patient is trained todistinguish (e.g., generate selectively) between the EEG patternsassociated with imagination of different simple motor actions, such asright or left hand movements. During the imagination of motion, specificcortical activity patterns (“cortical fingerprints”) for specificmovements are identified, for example a fingerprint for the motion ofpushing the hand forwards, in comparison to a fingerprint which isrecorded by moving the hand leftwards (or backwards, or upwards etc.).In an exemplary embodiment of the invention, in each of a series oftrials, the patient will imagine one of several actions (e.g. right orleft hand movement, forwards-backwards, left-right, diagonal, up-downmovements) while EEG from electrodes over sensorimotor cortex (or otherrecording sites) will be submitted to frequency- and/or componentanalysis (or other analysis methods) to derive signal features. For eachimagined action, an n-dimensional feature vector is optionally defined.These vectors are optionally used to establish a patient-specificclassifier that determines from the EEG which action the patient isimagining. Optionally, for each patient a “cortical fingerprintsmovement related dictionary” that matches a specific cortical activationto a specific movement is generated. Optionally, the movements arecarried out only in the mind. Alternatively or additionally, acomparison between imagined and actual motions is stored. Optionally, apatient stores such patterns before a paretic event, for example, aspart of a regular checkup or when danger is identified.

In subsequent sessions, the system can use the classifier (i.e. the“dictionary”) to translate the patient's motor imagery into a continuousoutput (e.g. moving the robot arm in the desired direction), and/or intoa discrete output (e.g. initiating robot movement). This output can bepresented to the patient as, for example, i) a sensory feedback throughhis hand, and/or ii) through online visual/acoustic feedback on thecomputer screen.

In another variation of this paradigm, the patient will actually movehis unaffected hand and/or the affected hand which is connected tosystem 600, or manipulator 604 will move the patient's hand during thesessions. A set of one or more dense electrodes arrays may be used torecord brain activity during these movements. This activity will becompared to the activity recorded during the imagined movements in orderto find correlations in brain activity during imagined and actualmovements. These “cortical fingerprints” of a movement will then beoptionally used to “guess” the patient's intention and to carry out thedesired movement.

Dosage

In an exemplary embodiment of the invention, the cortical effects areused to define a required dosage of rehabilitation and/or to controlbilling. In an exemplary embodiment of the invention, a match is madebetween an amount of activity by a user (for example, as measured byactual exercise time or cortical activity) and a therapeutic effectand/or a rehabilitation condition. In one example, 20 “active minutes”per day may be the dosage for medium severity pre-motor one damage.Optionally, a range of possible doses may be defined, for example a lowdosage not having sufficient effect and a high dosage possibly causingover compensation or undue tiredness. Optionally, the dosage is arelative dosage dependent on the patient's total ability and/or totalnumber of rehabilitation issues. Optionally, device 600 is used to trackthe actual applied dosage and/or its effect. Optionally, device 600 candistinguish the actual dosage applied to each area (or issue) in need oftreatment.

Optionally, the dosage is defined as a function of one or more ofphysical exertion mental exertion and/or attention/engagement.

Optionally, dosage is measured in units of one or more of power, forceor energy.

In an exemplary embodiment of the invention, device 600 is designed toapply a known amount of dosage and/or decide on changing an exerciseschedule, once a certain dosage is reached and/or to preventover-dosing.

In some cases, dosage is used to define a minimal level required toachieve benefit form rehabilitation, for example, a minimum exertionlevel or a minimal engagement level may be required.

In an exemplary embodiment of the invention, device 600 is used toensure such minimal attention/exertion levels.

In an exemplary embodiment of the invention, attention is measured bymeasuring compliance and/or variation in response time to instruction.Absolute response time may be of interest, for example, if there is anexpected response time based on previous activities.

While the present application focuses on physical activities, it shouldbe noted that the methods described herein can also be used forcognitive and perceptive rehabilitation, including the usage of dosage.In an exemplary embodiment of the invention, cognitive and/or perceptiveactivity is detected directly. Optionally, a patient is requested to doa physical activity to indicate the cognitive or perceptive activity.Optionally, the effect of motor signals in the brain is ignored and/orused as a trigger to search for brain activity related to a decision toprovide a response.

Mental State

In an exemplary embodiment of the invention, daily assessment of mentalstate is carried out as part of rehabilitation. In an exemplaryembodiment of the invention, brain image, blood tests and/or EEGmeasurements are used to assess an instant mental state of a patient,for example, depression or anxiety. Optionally, depending on themotivational state of the patient additional motivation may be providedand/or lesser achievements may be expected. It should be noted that thistype of depression relates to a mood, which can change hourly or dailyand not to clinical depression which is a long term illness.

In an exemplary embodiment of the invention, cognitive rehabilitationprogress is assessed using other means, such as problem solving or othercognitive tests. Optionally, cognitive progress is used to calibrateexpected physical rehabilitation progression, for example, assuming thata same improvement rate is expected for areas with similar damage undersimilar exercise protocols. Optionally, an improvement template isadjusted to match a patient based on improvement in one or morefunctions and used to estimate expected improvements in other functions.Optionally, a template includes a correspondence between expectedimprovement rates for areas of different degrees of damage and/ordegrees of accessibility to rehabilitation. Optionally, the template isadjusted according to actual rehabilitation effort.

In an exemplary embodiment of the invention, EEG measurements are usedto determine settings, environmental cues and/or exercises that promotedesired cortical brain activity and/or reduce noise that interferes withdetection thereof.

In an exemplary embodiment of the invention, the environmental cues areselected form one or more of colors, images, language, or other meansthat have been documented to cause certain types of emotional reactionsin people.

Optionally, a therapist and/or device 600 provide other motivationalmeans, such as motivational talks, movies and positive feedbackoptionally timed to have a desired effect.

In an exemplary embodiment of the invention, device 600 controlssimultaneously two or more of physical rehabilitation, brainstimulation, emotional control and instructions. Optionally, arehabilitation plan is optimized to take into account the parametersbeing controlled.

Motion Types

In device 600 as illustrated, the motion which is controlled isgenerally that of a single point, e.g., a tip of the manipulator. Byproviding various attachments for the tip, the tip may be connected, forexample to a bone, to a joint or to a different part of the body. Theattachment may be rigid, for example using a strap or it may depend oncooperation of or action by the patient, for example, as a handle or arest. Specific attachment devices, for example for a hand, arm, elbow,knee, ankle and/or shoulder may be provided. Further, as describedbelow, multiple tips (optionally with individual manipulators) may beprovided for attachment at different points of the body, on a same ordifferent body part.

When providing rehabilitation various types of motion may be supported,for example, one or more of:

a) Passive Motion. The tip is moved (by device 600) and the patientmoves with it.

b) Resisted Motion. The patient moves the tip and encounters resistance.The resistance may be of various magnitudes and may be uniform in alldirection or be directional.

c) Assisted Motion. When a patient moves the tip, a positive feedback onthe manipulator increases the force of motion in the direction moved bythe patient.

d) Force Field Motion. The patient moves the tip. Along a certaintrajectory one level of resistance (or none) is encountered. Deviationfrom the trajectory is not allowed or meets with resistance. Motionalong a “correct” trajectory can be without resistance, or possiblyassisted. An increased resistance is optionally exhibited in a volumesurrounding the trajectory. An even greater resistance is optionallyexhibited in a surrounding volume. A prevention of motion may beprovided in an outside volume. In an exemplary embodiment of theinvention, a corrective force vector is applied when not on thetrajectory, pointing towards the trajectory. Optionally, instead of acorrective force, resistance varies as a function of distance from thetrajectory, thus, motion of the tip is naturally urged back to thetrajectory. Optionally, the force is applied in the direction of thepath. Alternatively, the force maybe a unidirectional force ofresistance.

This type of motion may be used to help train the patient in a desiredmotion.

e) Mirrored Motion. Motion of the tip is required to mirror thetrajectory of motion of a different element, for example for dual limbrehabilitation as described below.

f) Free Motion. Patient moves the tip in any way he desires, possiblyreceiving feedback. As the patient (or therapist or helper) moves thetip, device 600, may record it for future playback. In a playback modethe prerecorded motion (or path) is optionally reconstructed using othermodes. Optionally, the recorded path is modified (e.g., smoothed orotherwise edited), for example automatically or manually.

g) General Force Field. A force field and/or an assistance field isdefined which is not related to any particular trajectory. For example,a range of trajectories may be allowed to be practiced by a user, or areal or virtual situation simulated (e.g., water, areas with obstacles).

h) Local Force Field. A force field which is applied to only a smalllocality and/or only in one or two dimensions.

i) Restricted Motion. One or more points of the body of a subject aresupported or prevented from moving. Optionally, the angles between suchpoints and the moving points on the patient are measured. In one examplethe elbow is locked with a dedicated harness allowing only a shouldermotion. In some embodiments, the restriction is partial and/or isprovided by a movable element (e.g., the manipulator).

j) Initiated Motion. The patient initiates the motion (e.g., a 1 cmmotion or 100 gram force) and device 600 completes or helps the patientcomplete the motion in space. The completion may be of a wholetrajectory or of part of a trajectory.

k) Implied Motion. Device 600 begins the motion and the patientcompletes it. Device 600 may assist the rest of the motion in variousmanners (e.g., by changing to one of the modes described herein afterthe motion starts). If the patient fails to pick up the motion, device600 may generate a cue, for example an audio reminder. Different partsof a single motion trajectory may each have a machine initiationdefinition. Optionally, if a patient is too slow in moving, device 600begins the motion.

l) Cued Motion. The patient receives a cue from the system before motionaccording to a different mode starts. The cue can be, for example,vibration of the tip, stimulation pads on the skin, audio or visual cue.In some embodiments of the invention, the strength of the cue and/or itstiming and/or other ongoing activities (e.g., a visual display and game)are used to help train the coordination between different modalities,for example, hand-eye coordination. A motion cue can be used to train akinesthetic sense.

m) Teach Mode. Device 600 is taught a motion. In one example, atherapist performs a motion and motion parameters at each point arerecorded and can then be used for an exercise. Another way of teachingthe system is to use a path that the therapist uses. The therapist mayuse a control to indicate a point to be taught or a continuous mode maybe defined by which an entire trajectory is learned. Optionally the pathand points are edited before replay. Optionally, the paths areabstracted, for example, by smoothing or identifying motion points,before playback.

n) Step Initiated. The patient initiates the motion (e.g., a 1 cm motionor 100 gram force) and device 600 completes or helps the patientcomplete the motion in space, however, patient initiated motion occursin steps and/or increments. In some exemplary embodiments of theinvention, a patient generated force in a predetermined “right”direction and/or range of directions must be applied at each step inorder for device 600 to complete and/or help the patient complete themotion. A “right” direction is optionally defined as one in which thepatient will receive a desired therapeutic benefit for moving in thatdirection. Optionally, the steps and/or increments are variable.Optionally, the steps and/or increments are pre-settable. Optionally,there is more than one “right” direction. The completion may be of awhole trajectory or of part of a trajectory.

o) Follow Assist. Device 600 is pre-programmed with at least one pointin a path of motion to be followed by the patient. In an exemplary modeof operation, patient initiates motion along the path of motion,optionally assisted by device 600. Motion along the path is optionallyconducted at a pre-set speed in some exemplary embodiments of theinvention. Optionally, the speed is not pre-set. Upon the arrival ofpatient at the pre-programmed point, motion by the patient in a “right”direction causes at least a brief acceleration in speed instigated bydevice 600. Optionally, a plurality of points are used to allow thepatient to “connect the dots” in the motion path. Optionally, “arrivalat a point” is determined considering vector of approach, speed ofapproach, elapsed time prior to arrival, and/or accuracy of arrival tothe point. Optionally, the patient must hold at the point steadily (i.e.no wobble) before being considered to have arrived at the point. In someexemplary embodiments of the invention, the patient is assisted withmovement along a predetermined proper path for therapy. In someexemplary embodiments of the invention, device 600 moves continuously ata predetermined speed and whenever the patient exerts a force above acertain level and/or in the right direction), the speed of the exerciseis increased.

General

While the above application has focused on motor training forrehabilitation, the methods and/or apparatus described herein may alsobe used for other applications. In an exemplary embodiment of theinvention, motor training is used for enhancing the control of musclesby athletes. Alternatively or additionally, motor training is used forenhancing motor control of musicians. Optionally, musical feedback isprovided during training and corresponding to the exercises. However, itshould be noted that some methods of the present invention findparticular utility in rehabilitation, especially when motor control isweak, patchy and/or non-existent.

Various designs for robots and positioning devices (e.g., hexapods) areknown in the art. It should be appreciated that various ones of thestatements described herein may be adapted for such robots and/orpositioning devices, in accordance with exemplary embodiments of theinvention. Alternatively or additionally, software may be provided forsuch robots and devices for carrying out various of the methodsdescribed herein, all in accordance with exemplary embodiments of theinvention.

In some embodiments of the invention, the systems described herein areused for uses other than rehabilitation, for example, task training,testing and/or robotic manipulation.

It will be appreciated that the above described methods ofrehabilitation may be varied in many ways, including, omitting or addingsteps, changing the order of steps and the types of devices used. Inaddition, a multiplicity of various features, both of method and ofdevices have been described. In some embodiments mainly methods aredescribed, however, also apparatus adapted for performing the methodsare considered to be within the scope of the invention. It should beappreciated that different features may be combined in different ways.In particular, not all the features shown above in a particularembodiment are necessary in every similar embodiment of the invention.Further, combinations of the above features are also considered to bewithin the scope of some embodiments of the invention. Also within thescope of the invention are kits which include sets of a device, one ormore limb holding attachments and/or software. Also, within the scope ishardware, software and computer readable-media including such softwarewhich is used for carrying out and/or guiding the steps describedherein, such as control of arm position and providing feedback. Sectionheadings are provided for assistance in navigation and should not beconsidered as necessarily limiting the contents of the section. Whenused in the following claims, the terms “comprises”, “includes”, “have”and their conjugates mean “including but not limited to”. It should alsobe noted that the device is suitable for both male and female, with malepronouns sometimes being used for convenience.

It will be appreciated by a person skilled in the art that the presentinvention is not limited by what has thus far been described. Rather,the scope of the present invention is limited only by the followingclaims.

1. A method of rehabilitation using a rehabilitation device, comprising:first instructing a person to carry out certain movements while beingcoupled to a robotic spatial manipulator using at least one of an audioprompt, an audio instruction, a display, stimulation of a nerve, CNSstimulation and mechanical vibration using the device; and, secondinstructing said robotic spatial manipulator to guide said person toperform an incorrect motion using the device.
 2. A method according toclaim 1, further comprising defining a rotational or translationalmapping between said movements and said incorrect movements.
 3. A methodaccording to claim 1, further comprising measuring a cortical responseto said person detecting said incorrect motion.
 4. A method according toclaim 1, where the incorrect motion is contrary to a planned motion ofthe person.
 5. A method according to claim 1, further comprisinginstructing the spatial manipulator to guide the person to perform partof a planned motion.
 6. A method according to claim 5, furthercomprising making the manipulator less active during the planned motionto see if the patient can at least one of compensate for the less activemanipulator and complete the planned motion.
 7. A method according toclaim 6, where making the manipulator less active means making themanipulator passive.
 8. A method according to claim 3, furthercomprising assessing the person's response by analyzing the measuredcortical response.
 9. A method according to claim 4, further comprisingchoosing the planned motion to generate at least one of an intendedcognitive activation to train a first, certain brain area.
 10. A methodaccording to claim 9, further comprising changing the planned motion togenerate at least one of an intended cognitive activation to train asecond, certain brain area.
 11. A method according to claim 4, furthercomprising using a graphical interface to at least one of plan andchange the planned motion.
 12. A method according to claim 4, furthercomprising showing feedback comprising an indication of brain activityduring planning of the planned activity to the person.
 13. A methodaccording to claim 12, further comprising showing the person progress inplanning ability using the feedback.
 14. A method according to claim 1,further comprising using the manipulator as an input device of theperson interacting with the device.
 15. A method according to claim 4,where the planned motion of the person is instigated by the devicestimulating the person to perform the planned motion.
 16. A methodaccording to claim 15, where the planned motion of the person ispreviously stored on a database for at least one of selection andretrieval by the device as part of a rehabilitation process.
 17. Amethod according to claim 4, further comprising ensuring mental imagery,comprising, providing the first instruction to a person which guides amental imagery of the person to perform the planned motion; measuringmovement of a person in response to the imagery; comparing said firstinstruction to the motion; and providing feedback to the personregarding said imagery.
 18. A method according to claim 17, comprisingmeasuring brain activity corresponding to said imagery.
 19. A methodaccording to claim 18, comprising comparing said brain activity to brainactivity collected during said motion.
 20. A method according to claim17, comprising changing the first instruction to prevent habitation ofsaid person.